MONTELUKAST EN RINITIS ALERGICA - AlergomurciaASMA RINITIS ALERGICA SANOS EOSINOFILOS / mm 2 P

1

Abril-04 MK y AlergiaMK y Alergia

MONTELUKAST EN MONTELUKAST EN

RINITIS ALERGICARINITIS ALERGICADr Juan Carlos Miralles López

Unidad de Alergología

Hospital Provincial Universitario. Murcia (España).

2


GRADO DE ACUERDO CON DISTINTAS AFIRMACIONES GRADO DE ACUERDO CON DISTINTAS AFIRMACIONES SOBRE EL ASMA:SOBRE EL ASMA: ALERGÓLOGOSALERGÓLOGOS

69 17 13

56 24 20

71 19 11

81 11 8

73 16 11

52 31 17

Muy+ Bastante de acuerdo Ni de acuerdo, ni en desacuerdo Muy+ Bastante en desacuerdo

El FVE1, y el PEF a menudo tienenuna escasa correlación con lossíntomas

Los pacientes cumplen mejor eltratamiento con comprimidosque con inhaladores

Sería muy útil disponer de un Sería muy útil disponer de un agente que tratara tanto el asma agente que tratara tanto el asma como la RAcomo la RA

El uso de 2 de larga duración puede producir tolerancia

Muchos pacientes no están controlados con el tratamiento

MK + ICS tiene un inicio de acción más rápido que doblar la dosis de ICS

3


** AproximadamenteAproximadamente el 80% el 80%

de de loslos asmasmááticosticos

presentanpresentan ssííntomasntomas de de

rinitisrinitis alaléérgicargica

BousquetBousquet J and the ARIA Workshop Group J Allergy Clin Immunol J and the ARIA Workshop Group J Allergy Clin Immunol 2001;108(5):S1472001;108(5):S147--S334; Sibbald B, Rink E Thorax 1991;46:895S334; Sibbald B, Rink E Thorax 1991;46:895--901; Leynaert 901; Leynaert B et al Am J Respir Crit Care Med 2000;162:1391B et al Am J Respir Crit Care Med 2000;162:1391--1396.1396.

AsmaAsmasólosólo

RinitisRinitis alérgicaalérgicasólosólo

RinitisRinitis alérgicaalérgica+ +

asmaasma

ASOCIACION ENTRE RINITIS ALÉRGICA Y ASMA

ASOCIACION ENTRE RINITIS ASOCIACION ENTRE RINITIS ALÉRGICA Y ASMAALÉRGICA Y ASMA

4


Prieto L, Gutierrez V, Morales C, Marin J. Differences in sensitivity, maximal response andposition of the concentration-response curve to methacholine between asthmatics, patientswith allergic rhinitis and healthy subjects. Respir Med. 1998 Jan;92(1):88-94.

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 withmethacholine . The test was interrupted when FEV1 dropped by more than 40% or when the highestconcentration 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% ofthe maximal response = position ) and level of plateau . The proportion of subjects with plateau wassignificantly 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 forasthmatics was (means +/- SD) 31.5 +/- 5.5%, compared with 20.8 +/- 8.1% in allergic rhinitics and13.7 +/- 6.7% in healthy subjects (P < 0.01). It was also higher in allergic rhinitics than in healthysubjects (P < 0.01). The EC50 values were decreased in asthmatics when they were compared witheither allergic rhinitics or healthy subjects (geometric mean EC50: asthmatics = 2.7 mg ml-1, allergicrhinitics = 6.2 mg ml-1, healthy subjects = 8.7 mg ml-1; P < 0.01), but no significant differences weredetected between allergic rhinitics and healthy subjects . These results demonstrate that in subjects withallergic 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 andallergic rhinitis may be a consequence of mechanisms that are at least partially different .

5


SENSIBILIDAD A METACOLINASENSIBILIDAD A METACOLINAASMA ASMA vsvs RINITIS ALÉRGICARINITIS ALÉRGICA

0,01

0,1

1

10

100

0,01

0,1

1

10

100

ASMAASMA R. ALERGICAR. ALERGICA

PC20

(m

g/m

l)PC

20 (

mg/

PC20

(m

g/m

lm

l ))

Prieto L. et al. Prieto L. et al. RespirRespir. . MedMed. 92: 88. 1998. 92: 88. 1998

P<0.01

SANOSSANOS

6


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 atopicasthmatics , atopic nonasthmatics and healthy controls . Eur Respir J. 1992 May;5(5):538 -44.

4 We studied the role of atopy , as defined by positive skin tests to common inhalantallergens , in allergic bronchial inflammation . Endobronchial biopsies were taken via thefibreoptic bronchoscope in 13 symptomatic atopic asthmatics , 10 atopic nonasthmatics , and7 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 celldegranulation , although less marked in atopic nonasthmatics , was a feature of atopy in general. The numbers of eosinophils , identified by immunohistochemical staining using themonoclonal 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 atopicgroups eosinophils showed ultrastructural features of degranulation . Measurements ofsubepithelial basement membrane thickness on electron micrographs showed that thecollagen layer was thickest in the asthmatics , intermediate in the atopic nonasthmatics andthinnest in the normals . The results suggest that airways eosinophilia and degranulation ofeosinophils 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 theclinical expression of this immune disorder .

7


0.1

1

10

100

1000

ASMAASMA RINITIS ALERGICARINITIS ALERGICA SANOSSANOS

EO

SIN

OF

ILO

S /

mm

EO

SIN

OF

ILO

S /

mm

22

P<0.005P<0.005 P<0.05P<0.05

P<0.0005

DjukanovicDjukanovic. Eur. . Eur. RespirRespir. J. 5: 538. 1992. J. 5: 538. 1992

Biopsia

bronquial

BiopsiaBiopsia

bronquialbronquial

INFLAMACION BRONQUIALINFLAMACION BRONQUIALRINITIS ALÉRGICARINITIS ALÉRGICA

N=13 N=10 N=7

8



0

2

4

6

8

10

ASMA RINITIS ALERGICARINITIS ALERGICA SANOS

P<0.05 P<0.005

P<0.0005

ME

MB

RA

NA

BA

SA

L

(m

)

DjukanovicDjukanovic. Eur. . Eur. RespirRespir. J. 5: 538. 1992. J. 5: 538. 1992

9


Prieto L, Gutierrez V, Uixera S. Exhaled nitric oxide and bronchial responsiveness toadenosine 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 subjectswith allergic rhinitis with and without increased responsiveness to direct and indirectbronchoconstrictor agents. STUDY DESIGN: Cross-sectional study with the order of challengetests randomized. SETTING: Specialist allergy unit in a university hospital. PATIENTS: Thirty-eightsubjects without asthma with allergic rhinitis and 10 healthy nonatopic control subjects. MEASUREMENTS AND RESULTS: Participants were challenged with increasing concentrations ofadenosine 5'monophosphate (AMP) and methacholine. ENO was measured with the single-exhalation method. A positive response to both bronchoconstrictor agents was detected in ninesubjects with allergic rhinitis, whereas four subjects showed increased responsiveness to AMP butnot 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 toboth 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 ofmethacholine or AMP causing a 20% fall in FEV(1). CONCLUSIONS: In subjects without asthmabut 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 resultssuggest that the presence of airway hyperresponsiveness is not the only factor that determines the increased NO levels detected in subjects with allergic rhinitis.

10



Rinitis alérgicaRinitis alérgica0

25

50

75

100

125

NO

EX

HA

LA

DO

(p

pb

)

P < 0.001

Sanos

Prieto L, et al. Prieto L, et al. ChestChest. 121: 1853. 2002. 121: 1853. 2002

N=38 N=10

11


Gaga M, Lambrou P, Papageorgiou N, Koulouris NG, Kosmas E, Fragakis S, Sofios C, RasidakisA, Jordanoglou J. Eosinophils are a feature of upper and lower airway pathology in non-atopicasthma, irrespective of the presence of rhinitis. Clin Exp Allergy. 2000 May;30(5):663-9.

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 thateosinophilia in the airways is a feature of rhinitic patients without asthma. OBJECTIVE: The aim ofour study was to examine whether cellular infiltration exists in the nasal mucosa of asthmaticseven in the absence of symptoms and signs of rhinitis. METHODS: Nasal mucosa biopsies weretaken from 27 non-atopic subjects and comprised nine asthmatic rhinitic patients (AR), eightasthmatic 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 whetherthere was an association between cellular infiltration in the nose and the lungs. The alkalinephosphatase-anti-alkaline phosphatase (APAAP) method was used on 6 microm thick cryostatsections 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 withcontrol 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 andthe airways (r = 0.851 P < 0.001). No differences in eosinophil numbers were detected betweenthe 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 eosinophilinfiltration 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 thesame disease entity.

12


INFLAMACION NASALINFLAMACION NASALPACIENTES ASMPACIENTES ASMÁÁTICOSTICOS

EOSI

NO

FILO

S EN

M

UCO

SA N

ASAL

Gaga M et al Clin Exp Allergy 2000;20:663Gaga M et al Clin Exp Allergy 2000;20:663--669.669.

18

16

14

12

10

8

6

4

2

0RinitisRinitis No rinitis SanosSanos

(n=9) (n=8) (n=10)

p<0.001

p<0.001

Asmáticos

13


Braunstahl GJ, Kleinjan A, Overbeek SE, Prins JB, Hoogsteden HC, Fokkens WJ. Segmentalbronchial provocation induces nasal inflammation in allergic rhinitis patients. Am J Respir CritCare Med. 2000 Jun;161(6):2051-7.

4 Allergic rhinitis and asthma often coexist and share a genetic background. Pathophysiologic connections between the nose and lungs are still not entirelyunderstood. This study was undertaken to compare allergic inflammation and clinicalfindings in the upper and lower airways after segmental bronchial provocation (SBP) in nonasthmatic allergic rhinitis patients. Eight nonasthmatic, grass pollen-sensitive patientswith allergic rhinitis and eight healthy controls were included. Bronchial biopsies and bloodsamples were taken before (T(0)) and 24 h (T(24)) after SBP. Nasal biopsies wereobtained at T(0), 1 h after SBP (T(1)), and T(24). Immunohistochemical staining wasperformed for eosinophils (BMK13), interleukin (IL)-5, and eotaxin. The number ofeosinophils 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 ofBMK13-positive and eotaxin-positive cells in the nasal lamina propria and enhancedexpression 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 healthycontrols. 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.

14


RESPUESTA A ALERGENORINITIS ALÉRGICA

RESPUESTA A ALERGENORESPUESTA A ALERGENORINITIS ALÉRGICARINITIS ALÉRGICA

0

5

10

15

20

25

30

35

40

45

BASAL 1h 24h

EO

SIN

OF

ILO

S /

mm

2

TIEMPO TRAS PROVOCACION

SANOS

RINITIS ALERGICARINITIS ALERGICA

P<0.05PROVOCACION SEGMENTARIA BRONQUIAL:BIOPSIA BRONQUIALBIOPSIA NASAL

PROVOCACION SEGMENTARIA BRONQUIAL:PROVOCACION SEGMENTARIA BRONQUIAL:BIOPSIA BRONQUIALBIOPSIA BRONQUIALBIOPSIA NASALBIOPSIA NASAL

BraunstahlBraunstahl. . AmAm. J. . J. RespirRespir. Crit. . Crit. CareCare MedMed. 161: 2051. 2000. 161: 2051. 2000

N=8

N=8

15


Braunstahl GJ, Overbeek SE, Kleinjan A, Prins JB, Hoogsteden HC, Fokkens WJ. Nasal allergenprovocation induces adhesion molecule expression and tissue eosinophilia in upper and lowerairways. J Allergy Clin Immunol. 2001 Mar;107(3):469-76.

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 ofeosinophils from the blood into the tissues is dependent on adhesion molecules . OBJECTIVE: To analyze the aspects of nasobronchial cross -talk, we studied the expressionof adhesion molecules in nasal and bronchial mucosa after nasal allergen provocation (NP). METHODS: Nine nonasthmatic subjects with seasonal AR and 9 healthy control subjectsunderwent 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 ofeosinophils , IL-5, eotaxin , intercellular adhesion molecule 1 (ICAM-1), vascular celladhesion molecule 1 (VCAM-1), E-selectin , and human endothelium (CD31). RESULTS: AtT(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 increasedpercentages of ICAM-1+, VCAM-1+, and E-selectin+ vessels , were seen in nasal andbronchial tissue of patients with AR. The number of mucosal eosinophils correlated with thelocal expression of ICAM-1, E-selectin , and VCAM-1 in patients with AR. CONCLUSION: Thisstudy shows that NP in patients with AR results in generalized airway inflammation throughupregulation of adhesion molecules .

16


RINITIS ALERGICARINITIS ALERGICAEFECTO DE PROV. NASAL CON ALERGENOEFECTO DE PROV. NASAL CON ALERGENO

0

10

20

30

40

50

60

70

80

90

ICAM-1+ VCAM-1+ ELAM-1+

BASAL TRAS PROVOCACION (24h)

Endotelio vascular:

Mucosa nasal

Mucosa bronquial

Endotelio vascular:Endotelio vascular:

Mucosa nasalMucosa nasal

Mucosa bronquialMucosa bronquial

P=0.01

P=0.04P=0.02

VA

SO

S P

OS

ITIV

OS

(%

)

BraunstahlBraunstahl. J. . J. AllergyAllergy ClinClin. . ImunolImunol. 107: 469. 2001. 107: 469. 2001

17


Chakir J, Laviolette M, Turcotte H, Boutet M, Boulet LP.Cytokine expression in the lowerairways of nonasthmatic subjects with allergic rhinitis: influence of natural allergen exposure. J Allergy Clin Immunol. 2000 Nov;106(5):904-10.

4 BACKGROUND: Natural exposure to pollen provokes an increase in airway responsivenessin 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 immunohistochemicaltests on bronchial biopsy specimens from subjects with rhinitis who had no past or currenthistory of asthma to evaluate cytokine expression and inflammatory cell numbers andactivation both in and out of the pollen season . RESULTS: The number of CD4(+), CD8(+), and CD45RO(+) lymphocyte subpopulations were significantly higher during the pollenseason compared with the out-of-season period (P <.04). Furthermore , EG1(+) cellstended to increase after natural pollen exposure (P =.06). The number of IL-5(+) cellsincreased significantly after natural exposure to pollen compared with out-of-seasonnumbers (P <.01). This increase in IL-5 expression was correlated with the numbers ofCD3(+), CD4(+), CD45RO(+), and EG1(+) cells . The numbers of tryptase -positive , IFN-gamma(+), and IL-4(+) cells did not change after natural exposure . CONCLUSION: Thisstudy showed that natural pollen exposure was associated with an increase in lymphocytenumbers , eosinophil recruitment , and IL-5 expression in the bronchial mucosa ofnonasthmatic subjects with allergic rhinitis .

18


INFLAMACION BRONQUIALINFLAMACION BRONQUIALRINITIS ALÉRGICA POLÍNICARINITIS ALÉRGICA POLÍNICA

0

5

10

15

20

25

30

FUERA ESTACION

ESTACION

CE

LU

LA

S /

mm

2

0

5

10

15

20

25

30

FUERA ESTACION

ESTACION

CE

LU

LA

S /

mm

2

CD4+CD4+CD4+ CD8+CD8+CD8+

P<0.01P<0.01 P<0.01

BIOPSIA BRONQUIALBIOPSIA BRONQUIAL

ChakirChakir J et al. J. J et al. J. AllergyAllergy ClinClin. . ImmunolImmunol. 106: 904. 2000. 106: 904. 2000

19


Prieto L, Uixera S, Gutierrez V, Bruno L. Modifications of airway responsiveness to adenosine5'-monophosphate and exhaled nitric oxide concentrations after the pollen season in subjectswith pollen-induced rhinitis. Chest. 2002 Sep;122(3):940-7.

4 STUDY OBJECTIVE:s : To determine the effect of cessation of exposure to pollen on airwayresponsiveness to adenosine 5'-monophosphate (AMP) in subjects with pollen -induced rhinitis , and toexplore 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 asthmawith pollen -induced rhinitis who showed bronchoconstriction in response to methacholine and AMP duringthe pollen season and 10 healthy nonatopic control subjects . MEASUREMENTS AND RESULTS: In subjectswith pollen -induced rhinitis , ENO concentrations , provocative concentration of agonist causing a 20% fallin FEV(1) (PC(20)) methacholine , and PC(20) AMP were determined during the pollen season and out ofseason . 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 to199.5 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). TheENO concentrations out of pollen season were still significantly increased in subjects with pollen -inducedrhinitis 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 foundbetween allergen -induced changes in ENO values and in airway responsiveness to either direct or indirectbronchoconstrictors . 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 .

20


EXPOSICION NATURAL AL ALERGENOEXPOSICION NATURAL AL ALERGENORINITIS ALÉRGICA POLÍNICARINITIS ALÉRGICA POLÍNICA

10

100

1000

ESTACION

NO

EX

HA

LA

DO

(p

pb

) P <0.001

FUERAESTACIONPrieto et al. Prieto et al. ChestChest. 122: 940. 2002. 122: 940. 2002

N=14

21


TogiasTogias A. Allergy 1999;54(suppl 57):94A. Allergy 1999;54(suppl 57):94--105.105.

Aspiración de secreciones inflamatoriasdesde la´VAS hacia losbronquios

Sustitución de respiración nasal por oral

Reflejo naso-bronquial

Liberación de mediadores a circulación sistémica que alcanzan losbronquios

RINITIS ALÉRGICA Y ASMAPOSIBLES MECANISMOS INTERACTIVOS

RINITIS ALRINITIS ALÉÉRGICA Y ASMARGICA Y ASMAPOSIBLES MECANISMOS INTERACTIVOSPOSIBLES MECANISMOS INTERACTIVOS

22


SENSIBILIZACIÓN A ALERGENOS INHALADOSSENSIBILIZACIÓN A ALERGENOS INHALADOSABORDAJE PARCELARABORDAJE PARCELAR

DIAGNOSTICO 1TRATAMIENTO 1DIAGNOSTICO 1DIAGNOSTICO 1TRATAMIENTO 1TRATAMIENTO 1



EVITACIÓN ALERGENOS

MODULACIÓN RESP. TH2

ANTAGONISTAS DE ILs

MONOCLONAL ANTI- IgE

ANTAGONISTAS DE LTs

EVITACIÓN ALERGENOS

MODULACIÓN RESP. TH2

ANTAGONISTAS DE ILs

MONOCLONAL ANTI- IgE

ANTAGONISTAS DE LTs

23

Abril-04 MK y AlergiaMK y AlergiaNayak AS, Philip G, Lu S, Malice MP, Reiss TF; Montelukast Fall Rhinitis Investigator Group . Efficacyand 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 AllergyAsthma Immunol . 2002 Jun;88(6):592 -600.

4 BACKGROUND: Histamine and cysteinyl leukotrienes seem to be important mediators of allergicrhinitis. OBJECTIVE: This multicenter, randomized, double-blind, parallel-group, placebo-controlled trial evaluated the effectiveness and tolerability of montelukast, loratadine, andcombination therapy with montelukast and loratadine for treating patients with fall seasonalallergic rhinitis. METHODS: After a 1-week, single-blind, placebo run-in period, 907 male andfemale 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 primaryendpoint was the daytime nasal symptoms score (mean of congestion, rhinorrhea, pruritus, andsneezing). RESULTS: Mean symptom scores at baseline were similar for the four treatmentgroups. 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 ofmontelukast/loratadine compared with loratadine alone, the primary comparison, was notsignificantly different. Differences for each therapy alone compared with placebo were alsosignificant for most secondary endpoints, including nighttime symptom scores, eye symptomsscores, and rhinitis-specific quality of life. Differences for montelukast/loratadine compared witheach therapy alone generally showed numerical superiority, and a few endpoints showeddifferences that were statistically significant. All active treatments showed a safety profilegenerally similar to placebo. CONCLUSIONS: Montelukast alone or in combination with loratadineis well tolerated and provides clinical and quality-of-life benefits for patients with seasonal allergicrhinitis.

24


NayakNayak AS et al Ann Allergy Asthma AS et al Ann Allergy Asthma ImmunolImmunol 2002;88(6):5922002;88(6):592--600.600.

Placebo

MontelukastMontelukast 10 mg 10 mg (n=155)(n=155)

Loratadina 10 mg (n=301)

–1 0 2Semanas después de aleatorización

Run-In Doble-ciego

Placebo (n=149)

Montelukast 10 mg + loratadina 10 mg (n=302)

EFICACIA DE MONTELUKASTRINITIS ALÉRGICA ESTACIONAL


25



0

–0.2

–0.4

–0.6m

edio

(S

E)

des

de

bas

alSíntomasSíntomas diadia

Placebo (n=149)Montelukast 10 mg (n=155)Loratadina 10 mg (n=301)Montelukast + loratadina (n=302)

p0.003p0.003

p0.003

p0.003p0.003

p0.003


EFICACIA DE MONTELUKASTEFICACIA DE MONTELUKASTRINITIS ALÉRGICA ESTACIONALRINITIS ALÉRGICA ESTACIONAL

SíntomasSíntomas nochenoche

Pb Mk+LtLtMk Pb Mk Mk+LtLt

26


*vs. placebo


0

–0.1

–0.2

–0.3

–0.4

–0.5

m

edio

des

de

bas

al

p0.001*p0.001*

p0.001 *

Placebo (n=148)

Montelukast10 mg

(n=151)

Loratadina10 mg (n=299)

Montelukast+ loratadina

(n=298)

EFICACIA DE MONTELUKASTEFICACIA DE MONTELUKASTRINITIS ALÉRGICA ESTACIONALRINITIS ALÉRGICA ESTACIONAL

Puntuación síntomas conjuntivalesPuntuación síntomas conjuntivales

27


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.

4 BACKGROUND: Inhaled corticosteroids (ICS) affect many inflammatory pathways in asthma but havelittle impact on cysteinyl leukotrienes . This may partly explain persistent airway inflammation duringchronic ICS treatment and failure to achieve adequate asthma control in some patients . This doubleblind , randomised , parallel group , non-inferiority , multicentre 16 week study compared the clinicalbenefits 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 inhaledbudesonide (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 groupsshowed 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 comparedwith 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 wassignificantly 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 groupsshowed similar improvements with respect to "as needed " beta agonist use, mean daytime symptomscore , nocturnal awakenings , exacerbations , asthma free days, peripheral eosinophil counts , and asthmaspecific quality of life. Both montelukast + budesonide and double dose budesonide were generally welltolerated . CONCLUSION: The addition of montelukast to inhaled budesonide is an effective and welltolerated alternative to doubling the dose of inhaled budesonide in adult asthma patients experiencingsymptoms and inadequate control on budesonide alone.

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ESTUDIO COMPACTESTUDIO COMPACTDISEÑO DEL ESTUDIODISEÑO DEL ESTUDIO

Montelukast 10 mg Montelukast 10 mg cadacada 24 h 24 h ++

BudesonidaBudesonida 400 400 µµg g cadacada 12 h12 h

Budesonida 800 µg cada 12 h

Budesonida 400 µg cada 12 h

Periodo IRun-in (4 sem) Ciego-simple

Periodo IITratamiento activo (12 sem) Doble-ciego

0 4 16

Semanas

1

n=448n=448

n=441n=441

8 12

29


ESTUDIO COMPACTESTUDIO COMPACTOBJETIVO DEL PRESENTE ANÁLISISOBJETIVO DEL PRESENTE ANÁLISIS

gDeterminar si el tratamiento con montelukastasociado a budesonida proporcionababeneficio adicional, comparado con budesonida sola, a los pacientes quepresentaban concomitantemente asma y rinitis alérgica

30


0.0

10.0

20.0

30.0

40.0

50.0

0 4 8 12

Cam

bio

s d

esd

e b

asal

(L/M

in,

LS

Med

ia ±

SE

M)

Montelukast (N=433)Budesonida (N=425)

Semanas

P=0.36

ESTUDIO COMPACTESTUDIO COMPACTMEJORÍA DEL PEF DE LA MAÑANAMEJORÍA DEL PEF DE LA MAÑANA

PoblaciónPoblación globalglobal

31


gg AsmaAsma y y RinitisRinitis alérgicaalérgica (AS/+RA)(AS/+RA)

Pacientes con asma y rinitis alérgica, definidapor una historia positiva y un diagnósticomédico.

gg AsmaAsma sin sin RinitisRinitis alérgicaalérgica (AS/(AS/--RA)RA)

Pacientes con asma sin una historia y un diagnóstico médico de rinitis alérgica.

ESTUDIO COMPACTESTUDIO COMPACTGRUPOS DE PACIENTES COMPARADOSGRUPOS DE PACIENTES COMPARADOS

32


0.0

10.0

20.0

30.0

40.0

50.0

0 4 8 12

Cam

bio

s d

esd

e b

asal

(L/M

in, L

S M

edia

± S

EM

)

Montelukast (N=216)

Budesonida (N=184)

Semanas

P<0.03


PoblaciónPoblación AS/+RAAS/+RA

33


-20.0

-10.0

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

0 4 8 12

Cam

bio

des

de

bas

al(L

/Min

, LS

Med

ia ±

SE

M)

Montelukast (N=33)Budesonide (N=23)

Semanas

P<0.02

*Esteroides intranasales o anti H1 u otros


PoblaciónPoblación AS/+RA con AS/+RA con tratamientotratamiento parapara rinitisrinitis**

34


CONCLUSIONESCONCLUSIONES

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 naso-oculares 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.

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