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

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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

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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

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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

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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

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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

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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.

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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

%)

.