Title: Bronchial asthma as neurogenic paroxysmal inflammatory disease - high efficacy of antiepileptic drug oxcarbazepine in asthma monotherapy
1Bronchial 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
2Asthma 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).
3Neurogenic 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?
4Antiepileptic 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).
5The 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
6Inclusion 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
-
7Exclusion 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
8Methods 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
9Methods 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
10Methods 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
11Patients
- 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.
12Statistical 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
-
13Baseline characteristics of patients
14Changes in PEF and FEV1
plt0.05
15Changes 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
16Changes in FEV1 after salbutamol inhalation
plt0.05
plt0.05
17Changes 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
18Frequency of EEG and neurological signs in
patients with asthma
19Adverse 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
20Next 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)
21Next 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
22Conclusions 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
23Conclusions 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
24Hypothesis 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 -
25Hypothesis 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
26Hypothesis 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
27Antiasthmatic mechanism of antiepileptic drugs -
a hypothesis
28Nature of bronchial asthma
- Is bronchial asthma peripheral disease with
definite central mechanism?
29Next studies in this direction are necessary
30References
- 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
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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.
31Asthma 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?
32EEG-symptoms in patients with asthma
33Neurological symptoms in patients with asthma
34Migraine and seizures in anamnesis of our
patients with asthma