2. Definition: Impaired function of the nose after
allergen exposure through
IgE-mediated allergic inflammation
Prevalence: 10-25%
Impacts
Social
Quality of life
Performance Schools
Cost 2Prof DR Dr Ariyanto Harsono SpAK
5. Arachidonic Acid
Phospholiphase A
Cyccloxygenase Lipoxygenase
Prostaglandine
TXA
Prostacyclin
Leukotriene A
Leukotriene B
Leukotriene C
Aspirin
2. Aspirin
HETE,5-HETE, PAF
5Prof DR Dr Ariyanto Harsono SpAK
7. Sel
Epitel
Makrofag
Sel T
Sel B
Sel Mast
Eosinofil
Gejala
Sitokin/Kemokin
IL-4, IL-5, IL-13,
IL-10, IL-3
GM-CSF,Eotaxin
RANTES,TGF-α,
TGF-β
Mediator
Histamin,
Prostaglandin
Leukotrien
Bersin,
Buntu,
Rinorea
Gatal
Infiltrasi Sel
Eosinofil
Inflamasi Alergi
Ko-morbid
7Prof DR Dr Ariyanto Harsono SpAK
34. Allergic Rhinitis and co-morbid conditions
Allergic rhinitis
Nasal polyps
Sleep disturbance,
including sleep-
disordered breathing
Rhinosinusitis (acute and chronic)
Asthma with AR
Congestion
Inflammation
Common cold
34Prof DR Dr Ariyanto Harsono SpAK
51. Treatment with desloratadine:
• Inhibition of allergic inflammatory
mediators
• Reduces symptoms of nasal
obstruction in the well-designed
studies
• Improve nasal airflow, an objective
measurement of the nasal
obstruction
51Prof DR Dr Ariyanto Harsono SpAK
52. 0
10
20
30
40
50
60
70
IL-6 IL-8 IL-3 GM-CSF
AERIUS
Cetirizine
Lippert U, et al. Exp Dermatol. 2000;9:118-124.
Percentinhibition
Desloratadine: Inhibition of Allergic
Inflammation
TNF-α
Greater inhibition than Cetirizine
Inhibition of Mast Cell Cytokine Release
52Prof DR Dr Ariyanto Harsono SpAK
53. Food Does Not Alter the Oral
Bioavailability of Desloratadine
Desloratadine 7.5 mg* after
high-fat, high-calorie meal
Desloratadine 7.5 mg* after
10-hour fast
MeanDesloratadine
PlasmaConcentration(µg/L)
0 4 8 12 16 20 24
0
1
2
3
4
Hour
Randomised, open-label, single-dose, 2-way crossover study (n = 18)
*The recommended daily dose for desloratadine is 5 mg.
Gupta S et al. Clin Pharmacokinet. 2002;41(Suppl 1):7-12. 53Prof DR Dr Ariyanto Harsono SpAK
54. 0 6 12 18 24
0
50
100
150
200
0
1
2
3
4
0 6 12 18 24
(µg/LPlasma)
Hours
FexofenadineDesloratadine
(ng/mLPlasma)
Banfield C et al. Clin Pharmacokinet. 2002:41:311-8.
Effect of Grapefruit Juice of
Desloratadine and Fexofenadine
Hours
With Grapefruit Juice
Without Grapefruit Juice
54Prof DR Dr Ariyanto Harsono SpAK
55. 0 4 8 12 16 20 24
0
1
2
3
4
5
6
Hour
DL 7.5 mg/d* + placebo
DL 7.5 mg/d* + erythromycin 500 mg TDS7
8
MeanDesloratadinePlasma
Concentration(µg/L)onDay10
DL, desloratadine; TDS, three times daily.
*The recommended daily dose for desloratadine is 5 mg.
Banfield C et al. Clin Pharmacokinet. 2002;41:29-35.
• Changes in AUC not
clinically significant
• Steady-state levels of DL
achieved by day 10 after
both treatments
Desloratadine/Erythromycin
Drug-Coadministration
55Prof DR Dr Ariyanto Harsono SpAK
56. ECG Pharmacodynamic Effects of
Desloratadine
• Desloratadine 45 mg* single daily doses
for 10 days; placebo crossover design
– No statistically significant differences in QTc
observed
• No clinically relevant adverse events reported
*Nine times the recommended daily dose.
ECG, electrocardiogram.
Bousquet J, et al.Allergy 2004;59 (suppl.77):4-16 56Prof DR Dr Ariyanto Harsono SpAK
57. Desloratadine and
EAACI/ARIA Criteria for Antihistamines
in Allergic Rhinitis
• AERIUS meets all EAACI-ARIA criteria for
antihistamines required for the treatment of allergic rhinitis
– Efficacy
• Effective in the treatment of intermittent and persistent rhinitis
• Effective for all nasal symptoms including nasal obstruction
• Improvement of eye symptoms
• Improvement in asthma symptoms
• Efficacy in pediatric and elderly patients
57Prof DR Dr Ariyanto Harsono SpAK
58. Desloratadine and
EAACI/ARIA Criteria for Antihistamines
in Allergic Rhinitis
- Safety and tolerability/side effects
• No sedation or cognitive or psychomotor impairment
• No anti-cholinergic effects
• No weight gain
• No cardiac side effects
• Studies should be carried out in young children and elderly
patients to assess safety
• Prospective postmarketing safety analysis should be conducted
58Prof DR Dr Ariyanto Harsono SpAK
60. Efficacy NASONEX in Pediatric
Patients with Perennial Allergic Rhinitis
• 4-week, double-blind study (double blind)
• With the extension of the 26-week, open-
label
• Children 3-11 years
• MFNS 100 mcg qd or placebo
60Prof DR Dr Ariyanto Harsono SpAK
61. Results Clinical Experience
NASONEX in Children
• Mometasone furoate nasal spray (MFNS) 100 mcg qd is the
optimal dose in children over 2 years
• Low potential for systemic effects
• There is no short-term growth disorders
• There is no evidence of HPA axis suppression
• Well tolerated
• Incidence of adverse events similar placebo
61Prof DR Dr Ariyanto Harsono SpAK
62. Efek Jangka Panjang Nasonex
thd Mukosa Hidung
AA BB
Before MFNS TreatmentBefore MFNS Treatment After 12 Months of TreatmentAfter 12 Months of Treatment
With MFNSWith MFNS
Minshall E, et al.Minshall E, et al. Otolaryngol Head Neck Surg.Otolaryngol Head Neck Surg. 1998;118(5):6481998;118(5):648
62Prof DR Dr Ariyanto Harsono SpAK
In addition to histamine, mast cells are also a major source of inflammatory mediators; the release of these inflammatory mediators may exacerbate allergic reactions induced primarily by histamine1 Inflammatory mediators released by mast cells include interleukins, tumor necrosis factor alpha (TNF α ), prostaglandins, and leukotrienes2 These inflammatory mediators promote endothelial cell activation, vasodilation, and movement of inflammatory cells from the circulation into tissues (extravasation)3 Illustration courtesy of Prof. M. Maurer. Kovarova and Rivera. Curr Med Chem. 2004;11:2083. Monroe et al. J Allergy Clin Immunol . 1997;99:S798-S806. Piconi et al. Int Arch Allergy Immunol . 2002;128:59.
The mechanism of nasal obstruction involves the action of a number of mediators, cytokines, and inflammatory cells involved in the allergic cascade, as shown in this slide. The pathophysiology of the early-phase response is primarily driven by preformed mediators (eg, histamine, tryptase, bradykinin), which contribute to airway oedema and subsequent symptoms of congestion and rhinorrhoea.[1] Histamine induces local nociceptive type C neurons by binding to neuronal H 1 receptors, which are found in the epithelium and submucosal regions.[1,2] Nerve endings release substance P and various peptides (eg, vasoactive intestinal polypeptide [VIP] and calcitonin gene-related peptide [CGRP]). Typical symptoms of the early-phase response are rhinorrhoea, sneezing, and itching, but nasal obstruction also has its origins at this stage. Pearlman DS. Pathophysiology of the inflammatory response. J Allergy Clin Immunol. 1999;104:S132-S137. Baraniuk JN. Pathogenesis of allergic rhinitis. J Allergy Clin Immunol. 1997;99:S763-S772.
Changes in nasal airflow and/or nasal architectural dynamics take place when allergic inflammation occurs in the nasal mucosa, but this is due to a combination of inflammation, increased vascular permeability, and congestion.[1] Release of certain early-phase mediators (eg, histamine, leukotrienes, kinins) causes increased vascular permeability and vasodilation in the nasal mucosa, resulting in mucosal oedema.[1] Vasodilation/vascular congestion is an important component of nasal obstruction, and it is quickly ameliorated in the short term with decongestants (ie, this is how decongestants are effective in nasal obstruction).[1] Release of allergic inflammatory mediators (ie, cytokines, chemokines, and adhesion molecules) associated with the late phase perpetuates the inflammatory response, of which nasal obstruction is the predominant symptom.[1] Nayak AS, Schenkel E. Desloratadine reduces nasal congestion in patients with intermittent allergic rhinitis. Allergy. 2001;56:1077-80.
Treatment options for nasal obstruction are limited to the H 1 -receptor antagonists, oral or topical decongestants, and topical nasal corticosteroids. We will discuss the advantages (pros) and disadvantages (cons) of each class of agents. Nayak AS, Schenkel E. Desloratadine reduces nasal congestion in patients with intermittent allergic rhinitis. Allergy. 2001;56:1077-80.
In this study, Horak and colleagues compared the effects of desloratadine and placebo on nasal airflow and SAR symptoms in response to grass pollen.[1] This graph demonstrates that the mean change from baseline in nasal obstruction scores was significantly reduced at 30 minutes with desloratadine therapy, an effect that persisted until the final measurement at 6 hours. Mean AUC for nasal obstruction scores for the desloratadine treatment group was also significantly lower than for the placebo group. Thus, nasal obstruction scores increased in response to allergen exposure, but this effect was blunted by desloratadine. The mean AUC for nasal symptom scores of rhinorrhoea and sneezing and for total nasal symptom scores during allergen exposure were significantly lower for desloratadine compared with placebo in both studies ( P < 0.001). Additionally, mean AUC for nasal secretion weights were significantly lower for desloratadine-treated patients compared with those receiving placebo. Desloratadine demonstrated a placebo-like safety profile. Horak F, Stubner UP, Zieglmayer R, Harris AG. Effect of desloratadine versus placebo on nasal airflow and subjective measures of nasal obstruction in subjects with grass pollen-induced allergic rhinitis in an allergen-exposure unit. J Allergy Clin Immunol . 2002;109:956-61.
In vitro data demonstrate that desloratadine inhibits allergic inflammatory mediators and reduces nasal obstruction symptoms in well-designed clinical studies. As demonstrated in these clinical studies, there is a consistent benefit on symptoms of nasal obstruction, which correlates with an improvement in nasal airflow.
Di dalam menginhibisi pelepasan cytokine mast cell, Aerius menunjukkan kemampuan inhibisi yang lebih besar dibandingkan dengan Cetirizine
Konsentrasi Aerius pada plasma darah adalah tidak dipengaruhi oleh makanan. Hal tersebut dibuktikan oleh penelitan yang dilakukan oleh Gupta dan kawan-kawan dimana pasien yang mendapatkan Aerius 7,5mg setelah puasa 10 jam memiliki konsentrasi Aerius pada plasma darah yang tidak berbeda dengan pasien yang mendapatkan Aerius 7,5 mg setelah mengkonsumsi makanan tinggi lemak dan tinggi kalori
Dari penelitian Banfield, menunjukkan bahwa konsentrasi Aerius pada plasma darah pasien yang meminum Aerius dengan juice grapefruit adalah sama dengan pasien yang meminum Aerius tanpa juice fruit. Beda dengan fexofenadine yang konsentrasi obat di plasma darah menurun apabila diminum bersama juice grapefruit
Konsentrasi Aerius pada plasma darah jika diminum bersama obat yang lain seperti Erythromycin adalah tidak berbeda signifikan secara klinis.
Pada Pemberian Aerius sampai 9 kali dari dosis yang dianjurkan atau 45 mg per hari selama 10 hari tidak ditemukan adanya QT prolongation
NASONEX Slide Update 5th proof 12/06/00 Slide # Efficacy of Mometasone Furoate Nasal Spray (MFNS, NASONEX ® ) in Pediatric Patients With Perennial Allergic Rhinitis (PAR) In a 4-week, double-blind study evaluating the effectiveness of NASONEX in the treatment of PAR, 381 children 3 to 11 years of age were assessed for symptom relief and overall response to treatment following treatment with NASONEX 100 mcg qd or placebo. At the end of 4 weeks, 357 patients continued in a 26-week, open-label extension. All received NASONEX 100 mcg qd during the extension. Schering-Plough Corporation. Data on file
NASONEX Slide Update 5th proof 12/06/00 Slide # Clinical Experience With Mometasone Furoate Nasal Spray (MFNS, NASONEX ® ) in Children: Conclusions In summary, NASONEX 100 mcg once daily has been demonstrated to be effective and well tolerated for the treatment of children with allergic rhinitis. A dose of 100 mcg once daily was determined to be the optimum pediatric dose and is as effective as beclomethasone dipropionate (BDP) 84 mcg twice daily. Several studies support the excellent safety profile of NASONEX in children. No evidence of growth suppression was detected in either a knemometry study or a 1-year statural growth study. In addition, no evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression has been found in children treated with NASONEX, and plasma concentrations of NASONEX in children have been too low to formally calculate its bioavailability. Finally, NASONEX 100 mcg once daily has been found to be well tolerated in children, with incidences of adverse events comparable to placebo.
NASONEX Slide Update 5th proof 12/06/00 Slide # Long-Term Effects of Mometasone Furoate Nasal Spray (MFNS, NASONEX ® ) on Nasal Mucosa Because prolonged dermal application of topical corticosteroids has been reported to cause thinning of the epithelium, concerns have been raised about the safety of the nasal mucosa during prolonged intranasal corticosteroid use. Therefore, a year-long local safety study was conducted to determine the long-term effects of NASONEX on the nasal mucosa. Sixty-nine patients with perennial allergic rhinitis were treated over a 12-month period with NASONEX 200 mcg once daily. Nasal biopsies were performed before and after treatment, and in healthy subjects as a control. Figures A and B show before-and-after biopsies of a representative patient who was treated with NASONEX. Before treatment (Figure A), the epithelium is disturbed and heavy subepithelial inflammatory infiltration is present, particularly with eosinophils. Following 12 months of treatment (Figure B), the epithelium is pseudostratified, ciliated, and columnar, with no signs of atrophy. The subepithelial inflammatory infiltrate is significantly decreased with an absence of eosinophils. This local safety study also found that NASONEX did not cause atrophy of the nasal epithelium. Following 12 months of treatment, the percentage of intact, ciliated epithelium actually increased from 59% to 71% in patients who received NASONEX. Infiltration of inflammatory cells, particularly eosinophils, was significantly reduced by NASONEX. Minshall E, Ghaffar O, Cameron L, et al. Assessment by nasal biopsy of long-term use of mometasone furoate aqueous nasal spray (NASONEX) in the treatment of perennial rhinitis. Otolaryngol Head Neck Surg. 1998;118(5):648-654