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  1. 1. Bronchial asthma as neurogenic paroxysmal inflammatory disease - high efficacy of antiepileptic drug oxcarbazepine in asthma monotherapy Merab Lomia 1 , Manana Pruidze 2 , Zaza Chapichadze 3 1 “Rea” Rehabilitation Centre, Tbilisi, Georgia 2 Centre of Chinese Medicine, Tbilisi 3 Drug Agency, Ministry of Public Health, Tbilisi ERS Annual Congress, Copenhagen, Sept 17-21
  2. 2. Asthma and other neurogenic inflammatory diseases <ul><li>Neurogenic inflammation may play important role in mechanism of asthma (Joos et al, 2003). </li></ul><ul><li>Neurogenic inflammation plays important role in mechanisms of migraine (Hardebo, 1992) and trigeminal neuralgia (Strittmatter et al, 1997). </li></ul><ul><li>Asthma is an inflammatory disease with paroxysmal clinical picture (Canadian asthma consensus report, 1999). </li></ul><ul><li>Migraine and trigeminal neuralgia are inflammatory diseases with paroxysmal clinical picture (Krzhyzhanovskij, 1980). </li></ul>
  3. 3. Neurogenic inflammatory diseases, antiepileptic drugs and asthma <ul><li>The same mediators (glutamate, tryptophane, etc.) have equal activity in provoking or suppressing of asthma attacks, migraine attacks, trigeminal neuralgia attacks and epileptic seizures. </li></ul><ul><li>Some antiepileptic drugs are very effective in therapy of migraine (Hering, Kuritzky, 1992; Corbo, 2003) and trigeminal neuralgia (Dalessio , 1987; Spina, Perugi, 2004). </li></ul><ul><li>Are some antiepileptic drugs also effective in asthma therapy? </li></ul>
  4. 4. Antiepileptic drugs and asthma <ul><li>Our previous results and other data confirm our hypothesis: </li></ul><ul><li>Carbamazepine and valproates are highly effective in asthma monotherapy (Lomia et al, 2004). </li></ul><ul><li>Treatment of children with epilepsy and concomitant asthma by antiepileptic drugs significantly reduces severity of asthma (Ivanova, 1987). </li></ul>
  5. 5. The aims and design of the study <ul><li>To establish the efficacy of oxcarbazepine in pharmacotherapy of adult patients with chronic asthma </li></ul><ul><li>To establish the frequency of EEG and neurological signs in adult patients with bronchial asthma </li></ul><ul><li>Double-blind, randomized, placebo-controlled study </li></ul>
  6. 6. Inclusion criteria <ul><li>Adult patients with bronchial asthma (aged 17-73 years, 23 men, 23 women) were enrolled into the study </li></ul><ul><li>Bronchial asthma has been known at least for 1 year </li></ul><ul><li>Absence of long-term remissions of asthma (lasting more than 1 month) </li></ul><ul><li>Poorly controlled asthma, due to various reasons </li></ul>
  7. 7. Exclusion criteria <ul><li>Presence of concomitant severe diseases </li></ul><ul><li>Allergy or intolerance to oxcarbazepine or carbamazepine </li></ul><ul><li>Age younger than 16 years old </li></ul><ul><li>Permanent use of long-term beta-agonists </li></ul><ul><li>Long-term history of smoking </li></ul><ul><li>Pregnancy or lactating </li></ul>
  8. 8. Methods: randomization and medication <ul><li>Randomized, placebo-controlled, double-blind study </li></ul><ul><li>Randomization: computer-generated </li></ul><ul><li>Initial 2-week run-in period </li></ul><ul><li>3 months (13 weeks) treatment period </li></ul><ul><li>Medication (capsules): </li></ul><ul><ul><ul><li>oxcarbazepine (300 mg) </li></ul></ul></ul><ul><ul><ul><li>placebo </li></ul></ul></ul>
  9. 9. Methods: dose titration and use of other antiasthmatic drugs <ul><li>Dose titration till 1-2 caps. 2 times a day - first 10-15 days </li></ul><ul><li>Patients were allowed to abandon any other previously prescribed routine antiasthmatic treatment in case of asthma symptoms disappearance, lasted at least 1 month after beginning the trial </li></ul>
  10. 10. Methods: registered data <ul><li>PEF am, pm - every day (Mini-Wright flow-meters) </li></ul><ul><li>FEV 1 - every week in the morning </li></ul><ul><li>FEV 1 before and after use of inhaled salbutamol - before and after the study in the morning </li></ul><ul><li>EEG-mapping and neural signs - before the study </li></ul><ul><li>Routine blood analysis - every month </li></ul><ul><li>Diary card: </li></ul><ul><ul><ul><li>daytime asthma symptom scores (0-3) </li></ul></ul></ul><ul><ul><ul><li>nighttime awakening due to asthma (0-1) </li></ul></ul></ul><ul><ul><ul><li>PEF am, pm </li></ul></ul></ul><ul><ul><ul><li>adverse events </li></ul></ul></ul>
  11. 11. Patients <ul><li>55 patients eligible to participate in the trial: </li></ul><ul><li>oxcarbazepine group - 35 patients, </li></ul><ul><li>placebo group - 20 patients. </li></ul><ul><ul><li>9 patients were excluded: </li></ul></ul><ul><ul><li>3 from oxcarbazepine group: </li></ul></ul><ul><ul><li>2 - due to stable side effects - dizziness and somnolence </li></ul></ul><ul><ul><li>1 - due to non-compliance </li></ul></ul><ul><ul><li>6 from placebo group - due to non-compliance </li></ul></ul><ul><li>46 patients (32 of oxcarbazepine group and 14 of placebo group) completed the study. </li></ul>
  12. 12. Statistical analysis <ul><li>Wilcoxon signed rank test was used throughout for statistical analysis of non-parametric related data </li></ul><ul><li>Mann-Whithey U-test was used for analysis of non-parametric independent data </li></ul><ul><li>Student t-test for parametric data </li></ul><ul><li>A p-value  0.05 was considered significant </li></ul><ul><li>For statistical analysis of data we used SPSS for Windows (Release 11.0) </li></ul><ul><li>Data is presented as Mean ± Standard Deviation </li></ul>
  13. 13. Baseline characteristics of patients
  14. 14. Changes in PEF and FEV 1 *p < 0.05
  15. 15. Changes in daytime and nocturnal symptoms <ul><li>Patients without asthma symptoms: </li></ul><ul><li>Oxcarbazepine group (n=32): before the study - 0 </li></ul><ul><li> after the study - 25 (78%) </li></ul><ul><li>Placebo group (n=14): before and after the study - 0 </li></ul>*p < 0.05 *p < 0.05
  16. 16. Changes in FEV 1 after salbutamol inhalation *p < 0.05 *p < 0.05
  17. 17. Changes in use of other concomitant antiasthmatic medication *p < 0.05 **p < 0.01 25 patients (78%) from oxcarbazepine group received only oxcarbazepine as antiasthmatic drug last 6-8 weeks at the end of the study
  18. 18. Frequency of EEG and neurological signs in patients with asthma
  19. 19. Adverse events <ul><li>Transient and mild adverse events - </li></ul><ul><li>in 6 patients (2 men and 4 women) - </li></ul><ul><li>only in first 2 weeks after the beginning of the study </li></ul><ul><li>dizziness - in 2 cases (women)* </li></ul><ul><li>somnolence - in 1 cases (man)** </li></ul><ul><li>headache - in 2 cases (1 man, 1 woman)* </li></ul><ul><li>somnolence and headache - in 1 case (woman)* </li></ul><ul><li>* - oxcarbazepine group, ** - placebo group </li></ul>
  20. 20. Next open-label observation - I <ul><li>All 25 responder patients from oxcarbazepine group continued therapy with oxcarbazepine </li></ul><ul><li>After 1-3 months from the end of the study 20 patients gradually changed oxcarbazepine to carbamazepine (due to economical reason) </li></ul>
  21. 21. Next open-label observation - II <ul><li>After 3 years: </li></ul><ul><li>All 25 responder patients (78%) from 33 patients of oxcarbazepine group have no symptoms of asthma </li></ul><ul><li>20 patients do not receive any drugs, including oxcarbazepine or capbamazepine </li></ul><ul><li>5 patients still receive only carbamazepine as antiasthmatic drug </li></ul>
  22. 22. Conclusions I <ul><li>Oxcarbazepine as antiasthmatic drug in 78% of cases: </li></ul><ul><li>Increases PEF and FEV 1 rates up to normal level </li></ul><ul><li>Reduces asthma symptoms down to complete remission </li></ul><ul><li>Reduces need of any other antiasthmatic therapy as far as complete abandoning </li></ul><ul><li>EEG and neurological signs in adult patients with asthma: </li></ul><ul><li>69.6% have EEG-signs </li></ul><ul><li>87% have neurological signs </li></ul>
  23. 23. Conclusions II <ul><li>Some antiepileptic drugs are much better in comparison with other antiasthmatic drugs, because </li></ul><ul><li>antiepileptic drugs in 70-80% of cases show next results: </li></ul><ul><li>No asthma symptoms </li></ul><ul><li>Nearly normal lung function </li></ul><ul><li>No need of other antiasthmatic drugs </li></ul><ul><li>Minimal or no side effects </li></ul><ul><li>No limitation of physical activities </li></ul><ul><li>No emergency visits to doctors </li></ul><ul><li>No limitation of trigger factors, including allergens </li></ul>
  24. 24. Hypothesis: asthma as neurogenic inflammatory paroxysmal disease - I <ul><li>Bronchial asthma is a paroxysmal neurogenic inflammatory disease with the complex pathogenic mechanism, including two levels of components: </li></ul><ul><li>1) multiple trigger components ( including allergy, </li></ul><ul><li>exercises, weather, etc. ), and </li></ul><ul><li>2) central neurogenic generator component of paroxysmal attacks of bronchial constriction and concomitant inflammation </li></ul>
  25. 25. Hypothesis: asthma as neurogenic inflammatory paroxysmal disease - II <ul><li>Under the influence of trigger components the paroxysmal generator component is induced and pathologic process appears: </li></ul><ul><li>with manifestation of periodic paroxysmal bronchial smooth muscles spasms, induced by the central structures of autonomic nervous system, and </li></ul><ul><li>with concomitant chronic neurogenic inflammation </li></ul>
  26. 26. Hypothesis: asthma as neurogenic inflammatory paroxysmal disease - III <ul><li>Vicious cycle is formed: trigger components provoke activity of generator component and vice versa </li></ul><ul><li>This is a mechanism of sustaining of asthma as a chronic disease. Abnormally increased vagal tone during asthma prevents generalization of paroxysmal activity into other parts of central nervous system </li></ul><ul><li>Constitutional predisposition to the development of neurogenic generator component is necessary for asthma development </li></ul>
  27. 27. Antiasthmatic mechanism of antiepileptic drugs - a hypothesis
  28. 28. Nature of bronchial asthma <ul><li>Is bronchial asthma peripheral disease with definite central mechanism? </li></ul>
  29. 29. Next studies in this direction are necessary <ul><li>Thank you </li></ul>
  30. 30. References <ul><li>Joos GF, De Swert KO, Schelfhout V , Pauwels RA. The Role of Neural Inflammation in Asthma and Chronic Obstructive Pulmonary Disease. Ann NY Acad Sci 2003: 992: 218-230. </li></ul><ul><li>Hardebo JE. A cortical excitatory wave may cause both the aura and the headache of migraine [review]. Cephalalgia 1992: 12(2): 75-80. </li></ul><ul><li>Strittmatter M, Grauer M, Isenberg E, Hamann G, Fischer C, Hoffmann KH, et al. Cerebrospinal fluid neuropeptides and monoaminergic transmitters in patients with trigeminal neuralgia. Headache 1997: 37(4): 211-216. </li></ul><ul><li>Canadian asthma consensus report. CMAJ 199: 161 (11Suppl): S1-S5. </li></ul><ul><li>Kryzhanovskii GN. Determinant structures in pathologic conditions of the nervous system. Generator mechanisms of neuropathologic syndromes. Meditsina, Moscow, 1980. </li></ul><ul><li>Hering R. Kuritzky A. Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo . Cephalalgia 1992: 12(2): 81-84. </li></ul><ul><li>Corbo J. The role of anticonvulsants in preventive migraine therapy. Curr Pain Headache Rep 2003 : 7(1): 63-66. </li></ul><ul><li>Dalessio DJ. The major neuralgias, postinfection neuritis, and atypical facial pain. In : Dalessio DJ, ed. Wolff’s Headache and Other Head Pain. Oxford University Press, Oxford, New York 1987; 266-288. </li></ul><ul><li>Spina E, Perugi G. Antiepileptic drugs: indications other than epilepsy (review). Epileptic Disorders 2004: 6(2): 57-75. </li></ul><ul><li>Lomia M, Chapichadze Z., Pruidze M. Efficacy of monotherapy with anticonvulsive drugs topiramate and carbamazepine in bronchial asthma: is asthma a neurological disease? Eur Respir J 2004: 24 Suppl 48: S130. </li></ul><ul><li>Lomia M, Pruidze M, Chapichadze Z. Bronchial asthma as neurogenic paroxysmal disease - high effectiveness of carbamazepine in asthma monotherapy. Eur Respir J 2004: 24 Suppl 48: S221. </li></ul><ul><li>Ivanova NA. Epilepsy in structure of concomitant diseases in children with bronchial asthma and principles of complex therapy [Russian]. In: Modern principles of treatment of children with relapsing and chronic bronchial and lungs diseases. Leningrad, 1987, 89-91. </li></ul>
  31. 31. Asthma and breath-holding spells: paroxysmal respiratory diseases <ul><li>Bronchial asthma and breath-holding spells (BHS): </li></ul><ul><li>vagal tone is high due to autonomic dysregulation </li></ul><ul><li>paroxysmal clinical picture </li></ul><ul><li>expiratory flow is impaired (dyspnoea in asthma and temporary apnoea in BHS) </li></ul><ul><li>antiepileptic agents are highly effective in monotherapeutic mode </li></ul><ul><li>Is BHS an intermediate form between asthma and epilepsy? </li></ul>
  32. 32. EEG-symptoms in patients with asthma
  33. 33. Neurological symptoms in patients with asthma
  34. 34. Migraine and seizures in anamnesis of our patients with asthma