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Common Allergy Update 2001 Asst. Prof. Kiat Ruxrungtham, M.D. Division of Allergy and Clinical Immunology Department of Medicine Faculty of Medicine Chulalongkorn.

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Presentation on theme: "Common Allergy Update 2001 Asst. Prof. Kiat Ruxrungtham, M.D. Division of Allergy and Clinical Immunology Department of Medicine Faculty of Medicine Chulalongkorn."— Presentation transcript:

1 Common Allergy Update 2001 Asst. Prof. Kiat Ruxrungtham, M.D. Division of Allergy and Clinical Immunology Department of Medicine Faculty of Medicine Chulalongkorn University

2 Allergic Rhinitis Allergic Rhinitis Allergic Asthma Allergic Asthma Atopic Dermatitis Atopic Dermatitis Urticaria Urticaria Food Allergy Food Allergy Drug Allergy Drug Allergy Allergy Chula 1999

3 Epidemiology of Allergic Diseases in Thai Children 2533; 2541

4 Mediators of Mast Cells and Basophils Histamine Tryptase Chymotryptase Heparin/Chondroitin Kininogenase Chemotactic Factors Prostaglandins Leukotrienes PAF Histamine RFs IL-3, 4, 5, 6, 7, 8 GM-CSF, TNF Chemokines - MCP1, MIP1 Oxygen radicals Primary Mediators Secondary Mediators Sim TC, Grant JA 1996 AllergyChula

5 Mediators of Mast Cells and Allergy Mast Cell Basophil Blood Vessels Smooth Muscles Mucus Glands Sensory Nerves LeukocytesLeukocytes H, PGD 2, LTs, PAF bradykinin H H, PGD 2, LTs, PAF LTB4PAF IL3, IL5 Chemokines Urticaria, Angioedema Laryngeal edema, Shock Bronchospasm Abd. pain, Vomiting Diarrhea, Rhinorhea Bronchial secretion Itching Inflammation - LPAR AllergyChula

6 Pathogenesis of Allergic Disease Genetic Susceptibility Allergic Sensitzation Upper/lower airway or Skin hyperresponsiveness Allergic Diseases Allergen Exposure Adjuvant factors : Tobacco smoke Air pollutants Lack of protective factors: Infection ? Immunization ? Nutrition ? Pollutants Infection Excercise Modified from Ulrich Wahn 1998 Vary in spectrum and severity

7 Principle Pathogenesis of Allergic Diseases Th-2Th-1 IL-12 IFN- IL-5 IL-3 GM-CSF Eosonophil Mast cell IL-4 IgE B-cell APC Allergen CD4+ T-cell Late Phase Reaction _ + IgG Durham and Till 1998, Lu 1998, Drazen 1996 CD8+ cell AllergyChula IL-5 B-cell Allergen Tryptase, LTs MBP ECP, LTs Other cells

8 The Respiratory Tract Upper Respiratory Tract Structures - Nose > trachea - Sinuses, eustachian tubes - Ciliated mucosal lining l Functions - Conditioning the air - Defense Filtration Inflammatory reaction Immune reaction - Smell - Voice Lower Respiratory Tract Structures - Trachea > alveoli l Functions - Inhalation-exhalation - Gas exchange - Acid-base balance

9 Co-existence of Asthma and AR 306 former students with Allergic Rhinitis 84 former students with Asthma Asthma no AR no Greisner WA et al Allergy Asthma Proc 1998; 19:185-8 86 % 79 % 21 % 23-Years Follow-up Study of Former Brown University Students (N=738)

10 Ragweed Hay Fever with Seasonal Asthma Ragweed Hay Fever with Seasonal Asthma Upper-Lower Airway Linked Placebo Welsh et al. Mayo Clin Proc 1987;62:125-34

11 AR in Patients with Mild Asthma Treatment with intranasal corticosteroids : AR in Patients with Mild Asthma Treatment with intranasal corticosteroids : Effect on lower airway responsiveness P =0.04 Watson WTA et al J Allergy Clin Immunol 1993; 91:97-101 AllergyChula

12 Mean Changes in FEV1 (Litre) in Treated AR with Mild Asthma Corren J, et al J Allergy Clin Immuno 1997; 100:781-788 Morning (AM) * * * P=0.01 ** * <0.05

13 Ideal Antihistamines Safety No CNS toxicity No cardiotoxicity Pharmacology Specific H1 receptor blockade Additional potent anti- allergic/anti-inflammatory effects Rapid onset of action Long-acting No-tachyphylaxis No drug interaction No dose-adjustment required in special-risk groups Simons FE EAACI 1998 AllergyChula

14 PK and PD : Second-Third generation Antihistamines Drug Metabolism T1/2 (h)* Onset Peak Duration Terfenadine Liver 16-24 1-2 h 3-4 h 8-12 h Astemizole Liver 9.5 days 2 day 9-12d weeks Loratadine Liver 17-24 >1 h 4-8 h 24 h Cetirizine no (Kidney) 25 1 h 4-8 h 24 h Fexofenadine minimal 14.4 1 h 2-3 h 24 h Inhibition of Histamine-wheal/flare Kaliner M. Clin Geriatrics 1997; Simons FE, NEJM 1994 AllergyChula

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17 H 1 -Antagonists and Drug Interaction First-generation H1-Antagonists Potentiation of Sedation : Alcohol, sedative agents, hypnotics, antidepressants Potentiation of Sedation : Alcohol, sedative agents, hypnotics, antidepressants Potentiation of anticholinergic effect: Antidepressants Potentiation of anticholinergic effect: Antidepressants Second-generation H1-Antagonists (Terfenadine, astemizole, ebastine-animal model, but not loratadine) (Terfenadine, astemizole, ebastine-animal model, but not loratadine) Decrease hepatic metabolism and increase risk of cardiotoxicity: Decrease hepatic metabolism and increase risk of cardiotoxicity: Drugs that inhibit cytochrome p450 : Ketoconazole, macrolides- erythromycin, other azoles- itraconazole Drugs that inhibit cytochrome p450 : Ketoconazole, macrolides- erythromycin, other azoles- itraconazole Drugs that prolong QT : quinidine Drugs that prolong QT : quinidine Third-generation H1-Antagonists (Cetirizine, Fexofenadine) No clinical significant in drug interaction No clinical significant in drug interaction AllergyChula

18 Antihistamines in Elderly Drawsiness, fatigue and may increase risk falling or accident The first-generation H1 antagonist should be avoided in patient with glaucoma The first-generation H1 antagonist should also be avoided in patient with prostrate hypertrophy Be aware of cardiotoxic risk; terfenadine, astemizole should be used with caution AllergyChula

19 Treatment of Allergic Rhinitis in Adults Allergy Immunol Clinic 2000

20 Allergy Chula 1999

21 Characteristics of Antihistamines AllergyChula H1 Antagonist +++ +++ Anticholinergic +++ - ( Cetirizine -dry mouth) Sedation ++/+++ - (Cetirizine +/-) Duration of Action +/++ ++/+++ (Astemizole-longest) (Astemizole-longest) Antiallergic -/+ -/++ (Azelastine) Antiinflammatory - -/+ (Clinical ?) (Citirizine, Loratadine (Citirizine, Loratadine Fexofenadine) Fexofenadine) Characteristics First Second/Third Generation

22 Adverse Effects of H 1 - Antagonists Adverse Effects CPM HZ TF ASZ LD CZ FX Sedation + ++ - - - -/+ - Appetite stim. - -/+ - -/++ - -/+ - Weight gain - -/+ - -/++ - -/+ - Dry mouth ++ + - - - -/+ - Prolong QTc -/ ? -/ ? +* +* - - - Torsade de Points - - +* +* - - - AllergyChula

23 Effects of fexofenadine, diphenhydramine, and alcohol on driving performance: in the Iowa driving simulator Overall driving performance Fexofenadine = placebo Alcohol >placebo Diphenhydramine > alcohol Drowsiness ratings were not a good predictor of impairment suggesting: drivers cannot use drowsiness to indicate when they should not drive. Weiler JM et al. Ann Intern Med 2000 Mar 7;132(5):354-63 AllergyChula

24 Sedation with "non-sedating antihistamines: four prescription- event monitoring studies in general practice N= a total of 43 363 patients: Drowsiness The Odd Ratio P value (versus Loratadine ) Fexofenadine0.63 (0.36-1.11)0.1 Acrivastine2.79 (1.69-4.58)<0.0001 Cetirizine3.53 (2.07-5.42)<0.0001 No increased risk of accident or injury was evident with any of the four drugs. Mann RD, et al. BMJ 2000 Apr 29;320(7243):1184-1187

25 Antihistamines in Elderly Drawsiness, fatigue and may increase risk falling or accident The first-generation H1 antagonist should be avoided in patient with glaucoma The first-generation H1 antagonist should also be avoided in patient with prostrate hypertrophy Be aware of cardiotoxic risk; terfenadine, astemizole should be used with caution AllergyChula

26 Anti-H1 and Anti-inflammation AntihistamineEvidence-based In VitroIn Vivo ( DPCT) (positive results/total) Loratadineyes1/3 Cetirizineyes3/5 Terfenadineyes1/1 Fexofenadineyesnd AllergyChula

27 GINA guidelines 1998 Focus on ICS and ß 2 -agonists Short-acting ß 2 prn Inhaled corticosteroids Long-acting ß 2 J Bousquet Berlin 1999 Intermittent Mild persistent Moderate persistent Severe persistent

28 Theophylline: Plasma concentrations Clinical Efficacy in Chronic Asthma as a monotherapy : –10-20 g/ml Anti-inflammatory, Immunomodulatory : –>5-10 g/ml Food and Drug Interaction Increase clearance: anticonvalsants (phenobarbital, phynytoin,carbamazepine), rifampicinIncrease clearance: anticonvalsants (phenobarbital, phynytoin,carbamazepine), rifampicin Decrease clearnace: alcohol, antibiotics (erythromycin, clarithromycin, ciprofloxacin), cimetidineDecrease clearnace: alcohol, antibiotics (erythromycin, clarithromycin, ciprofloxacin), cimetidine AllergyChula

29 Theophylline as an Add On Regimen (1) Evans DJ, et al N Engl J Med 1997; 13:1412-8 NS N=31 per group Budesonide: Low dose =400, High dose=800 BID** (**Decreased cortisol level) Theophylline: Low dose =250 mg BID (BW 80) *Median serum Theophylline =8.7 mg/ml

30 Theophylline as an Add On Regimen (2) 1997 Ukena et al Eur Respir J 1997; 10:2754-60 P<0.01 P=ns N= 69 N= 64

31 Pathogenesis of Allergy and Asthma and Potential Novel Therapy Leukotrienes PGD 2 Histamine Tryptase PAF Bronchoconstriction and Mucus Secretion Chemotaxis Eotaxin RANTES MCP4 Airway Hyperreactivity T-Helper Cells Th2 IL-5 IL-4 B Cells IgE Eosinophil Recruitment and Production Anti--IL-4 Ab IFN (Th1) Anti--IL-5 Ab Anti--leukotrienes Zileuton Zileuton Zafirlukast Zafirlukast Montelukast Montelukast Mast cell Tryptase inhibitor Anti-PAF IFN (Th1 switch) Eosinophil Inflammation

32 Future Options Phosphodiesterase 4 (PDE-4) inhibitors Theophylline is a non-selective PDE-4 inhibitorTheophylline is a non-selective PDE-4 inhibitor Selective inhibitors: CDP840, KF 19514, CP80, 633Selective inhibitors: CDP840, KF 19514, CP80, 633 –Increase intracellular c-AMP –Decreased eosinophil survival (IL-5 induced) –Decreeased IL-4, IL-13 production Momose T 1998, Faissier L 1996, Shichijo M 1997

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34 1-2 (55 0 C) 1-2

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36 Principles of Allergen Immunotherapy AllergyChula Induction Maintenance Phase

37 Allergen IT: Literature Searched by Tittle Words in IGM (31 Oct 1998) AllergyChula

38 Efficacy of Venom Immunotherapy (VIT) (Protection from systemic reaction to the insect stings) % Efficcacy AllergyChula

39 Clinical Efficacy of AIT in Allergic Rhinitis (41 DBPC trials as by October 1998) AllergyChula

40 Indications of Allergen Immunotherapy Insect sting allergyInsect sting allergy Systemic reaction (absolute indication) Systemic reaction (absolute indication) Allergic rhinitis*Allergic rhinitis* Allergic asthma* (PFT >70% pred. value)Allergic asthma* (PFT >70% pred. value) AllergyChula * Dissatisfactory with avoidance + pharmacotherapy

41 Allergen Immunotherapy not proven effective in: Atopic Dermatitis Atopic Dermatitis Food Allergy Food Allergy Chronic Urticaria Chronic Urticaria AllergyChula

42 Pathogenesis of Allergy and Asthma and Potential Novel Therapy Leukotrienes PGD 2 Histamine Tryptase PAF Bronchoconstriction and Mucus Secretion Chemotaxis Eotaxin RANTES MCP4 Airway Hyperreactivity T-Helper Cells Th2 IL-5 IL-4 B Cells IgE Eosinophil Recruitment and Production Anti--IL-4 Ab IFN (Th1) Anti--IL-5 Ab Anti--leukotrienes Zileuton Zileuton Zafirlukast Zafirlukast Montelukast Montelukast Mast cell Tryptase inhibitor Anti-PAF IFN (Th1 switch) Eosinophil Inflammation

43 Factors Affecting Clinical Outcomes of Allergic Diseases AllergyChula Enivronmental Allergens Irritants Westernization Infection Viral Bacterial Treatment Anti-inflammatory Anti-allergic Relievers Compliance Avoidance Medication uses Allergic Diseases Remission Moderate Mild Severe Allergen Immunotherapy Genetic Degree of atopy Future Therapy


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