Post on 26-Dec-2015
Bronchial asthma as neurogenic paroxysmal inflammatory disease - high efficacy of antiepileptic drug
oxcarbazepine in asthma monotherapy
Merab Lomia1, Manana Pruidze2, Zaza Chapichadze3
1“Rea” Rehabilitation Centre, Tbilisi, Georgia2Centre 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 patientsOxcarbazepine group(n=32)
Placebo group (n=14) P value
Age (years) 44.4 2.8 43.5 5.2 NSGender:MaleFemale
17 (53.1%)15 (46.9%)
6 (42.9%)8 (57.1%)
NSNS
Duration of asthma (years) 12.61.5 14.91.9 NSSeverity of asthma MildModerateSevere
4 (12.5%)10 (31.3%)18 (56.3%)
2 (14.3%)4 (28.6%)8 (57.1%)
NSNSNS
PEF (L/min) 291112 27398 NSFEV1 (L) 1.621.05 1.590.94 NSConcomitant medication1.Theophylline group2.Beta-agonists3.Steroids4.Cromolyn sodium5.Antihistamines
18 (56.3%)16 (50%)17 (53.1%)7 (21.9%)10 (31.3%)
9 (64.3%)6 (42.9%)10 (71.4%)6 (42.9%)6 (42.9%)
NSNSNSNSNS
14
Changes in PEF and FEV1
Peak-flow rates (Wright-McKerrow scale)
415*383*
430*
338
321 321320321250
300
350
400
450
500
0 4 8 13
Weeks of study
PEFR
oxcarbazepinegroup
placebo group
FEV1 % predicted
67.3*
58.6*
75.4*
46.6 50.9 52.050.7
49.7
20
40
60
80
0 4 8 13
Weeks of study
FE
V1 %
pre
dic
ted
*p*p<<0.050.05
15
Changes in daytime and nocturnal symptoms
Patients without asthma symptoms: Oxcarbazepine group (n=32): before the study - 0
after the study - 25 (78%) Placebo group (n=14): before and after the study - 0
*p*p<<0.050.05
Nights with awakening per week due to asthma
1.47*1.47*1.56*
4.22
3.643.86
3.433.64
1
2
3
4
0 4 8 13
Weeks
Nig
hts
Daytime scores of asthma (0-3)1.37
0,35*0,47*
0,48*
1.281.33
1.14
1.31
0
0.5
1
1.5
0 4 8 13
Weeks
Sco
res oxcarbazepine
group
placebo group
*p*p<<0.050.05
16
Changes in FEV1 after salbutamol inhalation
*p*p<<0.050.05
FEV1 changes in % after salbutamol inhalation
14.514.8
5.15*
15.7
0
5
10
15
20
before the study after the study
FEV
1 %
fro
m in
itia
l
leve
l
oxcarbazepinegroup
placebo group
*p*p<<0.050.05
17
Changes in use of other concomitant antiasthmatic medication
Oxcarbazepine group
56.3
12.5**
50
6.3*
53.1
21.9*21.9
9.4* 9.4*
31.3
0
20
40
60
before thestudy
after thestudy
% o
f p
ati
en
ts
Theophylline
Beta-agonists
Steroids
Cromoglycates
Antihistamines
Placebo group
64.3
42.9
64.342.9
64.371.4
42.9
5042.9
42.9
0
20
40
60
80
before thestudy
after thestudy
% o
f p
atie
nts
*p*p<<0.050.05
**p**p<<0.010.01
25 patients (78%) from oxcarbazepine group received 25 patients (78%) from oxcarbazepine group received onlyonly oxcarbazepine oxcarbazepine as antiasthmatic drug last 6-8 weeks at the end of the studyas antiasthmatic drug last 6-8 weeks at the end of the study
18
Frequency of EEG and neurological signs in patients with asthma
87.069.6
0
25
50
75
100
EEG-signs Neurological signs
% o
f pat
ient
s
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 IOxcarbazepine 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 IISome 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
Antiepileptic drugs suppress activity
CerebralGenerator factor
allows interactions
Trigger Bronchial factors reaction and
inflammation
Other antiasthmatic drugs
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. Wolff’s
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 modeIs BHS an intermediate form between asthma
and epilepsy?
32
EEG-symptoms in patients with asthma
13
19.6
41.3
8.7
15.2
17.4
0 10 20 30 40 50
Elevation index of alpha-band
Elevation index of beta-band
Elevation index of slow wave band
Interhemispheric asymmetry of EEG
Weakening of the reaction of activation
Decrease of the EEG voltage
Frequency of signs (in %)
33
Neurological symptoms in patients with asthma
19.6
37.0
34.8
39.1
35.0
34.8
0 10 20 30 40 50
Pyramidal pathological reflexes
Facial asymmetry
Chvostek reflex
Marinesku-Radovichi reflex
Spastic deep reflexes
Asymmetry of deep reflexes
Frequency of signs (in %)
34
Migraine and seizures in anamnesis of our patients with asthma
10.9
6.5
0
5
10
15
20
Migraine Seizures
Fre
quency
(in
%)
.