Bronchial asthma as neurogenic paroxysmal inflammatory disease - high efficacy of antiepileptic drug oxcarbazepine in asthma monotherapy - PowerPoint PPT Presentation

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Bronchial asthma as neurogenic paroxysmal inflammatory disease - high efficacy of antiepileptic drug oxcarbazepine in asthma monotherapy

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Title: Bronchial asthma as neurogenic paroxysmal inflammatory disease - high efficacy of antiepileptic drug oxcarbazepine in asthma monotherapy


1
Bronchial asthma as neurogenic paroxysmal
inflammatory disease - high efficacy of
antiepileptic drug oxcarbazepine in asthma
monotherapy
  • Merab Lomia1,3, Manana Pruidze2, Zaza
    Chapichadze3
  • 1Rea Rehabilitation Centre, Tbilisi, Georgia
  • 2Centre of Chinese Medicine, Tbilisi
  • 3Drug Agency, Ministry of Public Health, Tbilisi
  • ERS Annual Congress, Copenhagen, Sept 17-21

2
Asthma and other neurogenic inflammatory diseases
  • Neurogenic inflammation may play important role
    in mechanism of asthma (Joos et al, 2003).
  • Neurogenic inflammation plays important role in
    mechanisms of migraine (Hardebo, 1992) and
    trigeminal neuralgia (Strittmatter et al, 1997).
  • Asthma is an inflammatory disease with paroxysmal
    clinical picture (Canadian asthma consensus
    report, 1999).
  • Migraine and trigeminal neuralgia are
    inflammatory diseases with paroxysmal clinical
    picture (Krzhyzhanovskij, 1980).

3
Neurogenic inflammatory diseases, antiepileptic
drugs and asthma
  • The same mediators (glutamate, tryptophane, etc.)
    have equal activity in provoking or suppressing
    of asthma attacks, migraine attacks, trigeminal
    neuralgia attacks and epileptic seizures.
  • Some antiepileptic drugs are very effective in
    therapy of migraine (Hering, Kuritzky, 1992
    Corbo, 2003) and trigeminal neuralgia (Dalessio,
    1987 Spina, Perugi, 2004).
  • Are some antiepileptic drugs also effective in
    asthma therapy?

4
Antiepileptic drugs and asthma
  • Our previous results and other data confirm our
    hypothesis
  • Carbamazepine and valproates are highly effective
    in asthma monotherapy (Lomia et al, 2004).
  • Treatment of children with epilepsy and
    concomitant asthma by antiepileptic drugs
    significantly reduces severity of asthma
    (Ivanova, 1987).

5
The aims and design of the study
  • To establish the efficacy of oxcarbazepine in
    pharmacotherapy of adult patients with chronic
    asthma
  • To establish the frequency of EEG and
    neurological signs in adult patients with
    bronchial asthma
  • Double-blind, randomized, placebo-controlled study

6
Inclusion criteria
  • Adult patients with bronchial asthma (aged 17-73
    years, 23 men, 23 women) were enrolled into the
    study
  • Bronchial asthma has been known at least for 1
    year
  • Absence of long-term remissions of asthma
    (lasting more than 1 month)
  • Poorly controlled asthma, due to various reasons

7
Exclusion criteria
  • Presence of concomitant severe diseases
  • Allergy or intolerance to oxcarbazepine or
    carbamazepine
  • Age younger than 16 years old
  • Permanent use of long-term beta-agonists
  • Long-term history of smoking
  • Pregnancy or lactating

8
Methods randomization and medication
  • Randomized, placebo-controlled, double-blind
    study
  • Randomization computer-generated
  • Initial 2-week run-in period
  • 3 months (13 weeks) treatment period
  • Medication (capsules)
  • oxcarbazepine (300 mg)
  • placebo

9
Methods dose titration and use of other
antiasthmatic drugs
  • Dose titration till 1-2 caps. 2 times a day -
    first 10-15 days
  • 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

10
Methods registered data
  • PEF am, pm - every day (Mini-Wright flow-meters)
  • FEV1 - every week in the morning
  • FEV1 before and after use of inhaled salbutamol -
    before and after the study in the morning
  • EEG-mapping and neural signs - before the study
  • Routine blood analysis - every month
  • Diary card
  • daytime asthma symptom scores (0-3)
  • nighttime awakening due to asthma (0-1)
  • PEF am, pm
  • adverse events

11
Patients
  • 55 patients eligible to participate in the trial
  • oxcarbazepine group - 35 patients,
  • placebo group - 20 patients.
  • 9 patients were excluded
  • 3 from oxcarbazepine group
  • 2 - due to stable side effects - dizziness and
    somnolence
  • 1 - due to non-compliance
  • 6 from placebo group - due to non-compliance
  • 46 patients (32 of oxcarbazepine group and 14 of
    placebo group) completed the study.

12
Statistical analysis
  • Wilcoxon signed rank test was used throughout for
    statistical analysis of non-parametric related
    data
  • Mann-Whithey U-test was used for analysis of
    non-parametric independent data
  • Student t-test for parametric data
  • A p-value ? 0.05 was considered significant
  • For statistical analysis of data we used SPSS for
    Windows (Release 11.0)
  • Data is presented as Mean Standard Deviation

13
Baseline characteristics of patients
14
Changes in PEF and FEV1

plt0.05
15
Changes in daytime and nocturnal symptoms
  • Patients without asthma symptoms
  • Oxcarbazepine group (n32) before the study - 0
  • after the study - 25 (78)
  • Placebo group (n14) before and after the study
    - 0

plt0.05
plt0.05
16
Changes in FEV1 after salbutamol inhalation
plt0.05
plt0.05
17
Changes in use of other concomitant antiasthmatic
medication
25 patients (78) from oxcarbazepine group
received only oxcarbazepine as antiasthmatic drug
last 6-8 weeks at the end of the study
plt0.05
plt0.01
18
Frequency of EEG and neurological signs in
patients with asthma

19
Adverse events
  • Transient and mild adverse events -
  • in 6 patients (2 men and 4 women) -
  • only in first 2 weeks after the beginning of the
    study
  • dizziness - in 2 cases (women)
  • somnolence - in 1 cases (man)
  • headache - in 2 cases (1 man, 1 woman)
  • somnolence and headache - in 1 case (woman)
  • - oxcarbazepine group, - placebo group

20
Next open-label observation - I
  • All 25 responder patients from oxcarbazepine
    group continued therapy with oxcarbazepine
  • After 1-3 months from the end of the study 20
    patients gradually changed oxcarbazepine to
    carbamazepine (due to economical reason)

21
Next open-label observation - II
  • After 3 years
  • All 25 responder patients (78) from 33 patients
    of oxcarbazepine group have no symptoms of asthma
  • 20 patients do not receive any drugs, including
    oxcarbazepine or capbamazepine
  • 5 patients still receive only carbamazepine as
    antiasthmatic drug

22
Conclusions I
  • Oxcarbazepine as antiasthmatic drug in 78 of
    cases
  • Increases PEF and FEV1 rates up to normal level
  • Reduces asthma symptoms down to complete
    remission
  • Reduces need of any other antiasthmatic therapy
    as far as complete abandoning
  • EEG and neurological signs in adult patients with
    asthma
  • 69.6 have EEG-signs
  • 87 have neurological signs

23
Conclusions II
  • Some antiepileptic drugs are much better in
    comparison with other antiasthmatic drugs,
    because
  • antiepileptic drugs in 70-80 of cases show next
    results
  • No asthma symptoms
  • Nearly normal lung function
  • No need of other antiasthmatic drugs
  • Minimal or no side effects
  • No limitation of physical activities
  • No emergency visits to doctors
  • No limitation of trigger factors, including
    allergens

24
Hypothesis asthma as neurogenic inflammatory
paroxysmal disease - I
  • Bronchial asthma is a paroxysmal neurogenic
    inflammatory disease with the complex pathogenic
    mechanism, including two levels of components
  • 1) multiple trigger components (including
    allergy,
  • exercises, weather, etc.), and
  • 2) central neurogenic generator component of
    paroxysmal attacks of bronchial constriction
    and concomitant inflammation

25
Hypothesis asthma as neurogenic inflammatory
paroxysmal disease - II
  • Under the influence of trigger components the
    paroxysmal generator component is induced and
    pathologic process appears
  • with manifestation of periodic paroxysmal
    bronchial smooth muscles spasms, induced by the
    central structures of autonomic nervous system,
    and
  • with concomitant chronic neurogenic inflammation

26
Hypothesis asthma as neurogenic inflammatory
paroxysmal disease - III
  • Vicious cycle is formed trigger components
    provoke activity of generator component and vice
    versa
  • 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
  • Constitutional predisposition to the development
    of neurogenic generator component is necessary
    for asthma development

27
Antiasthmatic mechanism of antiepileptic drugs -
a hypothesis

28
Nature of bronchial asthma
  • Is bronchial asthma peripheral disease with
    definite central mechanism?

29
Next studies in this direction are necessary
  • Thank you

30
References
  • 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.
  • Hardebo JE. A cortical excitatory wave may cause
    both the aura and the headache of migraine
    review. Cephalalgia 1992 12(2) 75-80.
  • 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.
  • Canadian asthma consensus report. CMAJ 199 161
    (11Suppl) S1-S5.
  • Kryzhanovskii GN. Determinant structures in
    pathologic conditions of the nervous system.
    Generator mechanisms of neuropathologic
    syndromes. Meditsina, Moscow, 1980.
  • Hering R. Kuritzky A. Sodium valproate in the
    prophylactic treatment of migraine a
    double-blind study versus placebo.
    Cephalalgia 1992 12(2) 81-84.
  • Corbo J. The role of anticonvulsants in
    preventive migraine therapy. Curr Pain Headache
    Rep 2003 7(1) 63-66.
  • Dalessio DJ. The major neuralgias, postinfection
    neuritis, and atypical facial pain. In Dalessio
    DJ, ed. Wolffs Headache and Other Head Pain.
    Oxford University Press, Oxford, New York 1987
    266-288.
  • Spina E, Perugi G. Antiepileptic drugs
    indications other than epilepsy (review).
    Epileptic Disorders 2004 6(2) 57-75.
  • 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.
  • 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.
  • 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.

31
Asthma and breath-holding spells paroxysmal
respiratory diseases
  • Bronchial asthma and breath-holding spells (BHS)
  • vagal tone is high due to autonomic dysregulation
  • paroxysmal clinical picture
  • expiratory flow is impaired (dyspnoea in asthma
    and temporary apnoea in BHS)
  • antiepileptic agents are highly effective in
    monotherapeutic mode
  • Is BHS an intermediate form between asthma and
    epilepsy?

32
EEG-symptoms in patients with asthma
33
Neurological symptoms in patients with asthma
34
Migraine and seizures in anamnesis of our
patients with asthma
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