EP1175209A2 - Nouvelle indication pour l'utilisation d'agents et de medicaments antiepileptiques - Google Patents

Nouvelle indication pour l'utilisation d'agents et de medicaments antiepileptiques

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Publication number
EP1175209A2
EP1175209A2 EP00922799A EP00922799A EP1175209A2 EP 1175209 A2 EP1175209 A2 EP 1175209A2 EP 00922799 A EP00922799 A EP 00922799A EP 00922799 A EP00922799 A EP 00922799A EP 1175209 A2 EP1175209 A2 EP 1175209A2
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Prior art keywords
bronchial
asthmatic
asthma
bronchial asthma
treatment
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EP00922799A
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German (de)
English (en)
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Merab Lomia
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • This invention refers to medicine, in particular to pharmacology and pharmacotherapy.
  • Antiepileptic agents and medicines are used in the following directions: for treating epilepsy, seizures and similar conditions, trigeminal and other neuralgia, hemicrania, breath-holding attacks, tic hyperkynesia, psychosis, abstinent syndromes and some other diseases (Mashkovskij MD. Medicinal Agents. Moscow, “Meditsina”, 1998).
  • the use of antihystamines for treatment of bronchial asthma, asthmatic and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndrome for treatment of diseases and pathological conditions with these syndromes (Mashkovskij MD. Medicinal Agents. Moscow, “Meditsina”, 1998).
  • beta-2 agonists for treatment of bronchial asthma, asthmatic and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndromes and for treatment of diseases and pathological conditions with these syndromes (Mashkovskij MD. Medicinal Agents. Moscow, “Meditsina”, 1998)
  • antiepileptic agents and their derivates and analogues, their tautomers and pharmaceutically accepted compounds separately or in combination with other agents as therapeutic means for treating of all types of bronchial asthma, asthmatic and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndromes and treatment of diseases proceeding with these syndromes and also for treatment of allergic and vasomotor rhinitis and rhinoconjunctivitis.
  • Antiepileptic agents with antiasthmatic properties include such agents as derivates, analogues and tautomers of 1) barbituric acid, 2) hydantoin (e.g. phenytoin, fosphenytoin), 3) pyrimidine (e.g. hexamidinum, primidone), 4) oxazolidinedione (e.g. trimethindione), 5) indandione (e.g. methindion), 6) succinimide (e.g. aethosuximide), 7) iminostilben (e.g. carbamazepine, oxcarbazepine), 8) butamsultham (e.g.
  • sultiam 9) 1,4 benzodiazepines (e.g. clonazepam), 10) 1,5 benzodiazepines (e.g. clobazam), 11) valproic acid and salts of valproic acid, 12) aminoindandions (e.g. methindione), 13) acethylcarbamate (e.g phenacemide), 14) beta- chlorpropionic acid (e.g. beclamide), 15) tetronic acid (e.g. losigamone), 16) sulfonamides (e.g. zonisamide), 17) fructose sulfamates (e.g. topiramate), 18) pyrrolidine (e.g.
  • levetiracetam 19) acetamides (e.g. remacemide hydrochloride), 20) propylene glycols (e.g. felbamate), 21) nipecotic acid (e.g. tiagabine), 22) triasines (e.g. lamotrigine), 23) gamma-aminobutyric acid (e.g. vigabatrin, gabapentin, progabide), 24) thiazoles (e.g.
  • ralitoline 25) selenazoles, 26) pirazoles, 27) izatine, 28) diphenylsulphone, 29) ethylselenazolidindione, 30) benzimidazolin-2tione, 31) dioxolanes (e.g. stiripentol), 32) azetidines, 33) triazoles (e.g. loreclezole), 34) acetamides (e.g. milacemide), 35) imidazoles (e.g. nafimidone) and other antiepileptic agents.
  • bronchial asthma is a chronic inflammatory disorder of the airways in which many cells play a role, in particular mast cells, eosinophils, and T-lymphocytes.
  • this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough particularly at night and/or in the early morning.
  • wheezing causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough particularly at night and/or in the early morning.
  • wheezing wheezing, breathlessness, chest tightness, and cough particularly at night and/or in the early morning.
  • These symptoms are usually associated with widespread but variable airflow limitation that is at least partly reversible either spontaneously or with treatment.
  • the inflammation also causes an associated increase in airway responsiveness to a variety of stimuli (Global Initiative for Asthma. National Institutes of Health. Global strategy for asthma management and prevention. NHLBIAVHO workshop report. Publication no. 95-3659, 1995).
  • asthma is unknown, and it is not even clear whether asthma is a single disease with a single cause or a symptom complex with many separate causes (Reed CE. Allergy and asthma. In: Sodeman's pathologic physiology. Mechanisms of disease. Ed.: W.A.Sodeman, T.A.Sodeman. W.B. Saunders Company. Philadelphia, London, Toronto, Mexico City, Rio de Janeiro, Sydney, Tokyo, Hong Kong, 1985).
  • Gafurov BG Rakhimdzhanov AR Epilepsy and functional status of brain [Russian].
  • Meditsina UzSSR Tashkent, 1985
  • bronchial reactivity O'Connor GT, Weiss ST, Speizer FE.
  • bronchial asthma can be considered as pathologic condition with paroxysmal clinical manifestation; paroxysms of bronchial asthma by the relative analogy with "Clinical and electroencephalographical classification of epileptic seizures” (Commission on Classification and Terminology of the International League against Epilepsy, 1981. Proposal for revised clinical and electroencephalographic classification of epileptic seizures.
  • Epilepsia 22: 489-501, 1981
  • reflexes from bronchial surface and in some cases from other sites, or psychogenic factors can cause centrally induced neurogenic (vagal, and not only vagal) paroxysmal bronchoconstriction with predominantly expiratory dyspnoe and neurogenic bronchial inflammation due to decreased excitation threshold of the corresponding areas of central nervous system.
  • This spasm (reflex or psychogenic) can be a result of the allergen effects with subsequent inflammation, or also intensive smell, cold air, emotional factors, physical e-xercise, signals from the interoceptors of other organs, etc.
  • the bronchial spasm is partial - it almost never is generalized and never accompanied with the disturbances of consciousness. Similar to the epileptic status an asthmatic status could be developed. Based on the above-mentioned considerations, we assume that:
  • Bronchial asthma is a disease with the complex pathogenic mechanism, including two components: 1) peripheral (allergic, reflex, physical exercise) and/or central (psychogenic) trigger component and 2) central neurogenic generator component of paroxyzmal attacks of bronchoconstriction and inflammation.
  • trigger components in case of constitutional predisposition to the development of generator component - decrease of threshold to the central neurogenic predisposition (susceptibility) to the paroxysmal bronchoconstriction and concomitant neurogenic inflammation
  • the paroxysmal generator component is induced and pathologic process maintained, manifesting itself with the periodic paroxysmal bronchial smooth muscles spasms, predominantly in the phase of expiration induced by the central nervous system. These spasms are clinically manifested by the paroxysmal attacks of specific predominantly expiratory dyspnoe and/or cpugh.
  • generator component results in the maintenance and stabilization of trigger components, manifested in the additional neurogenic induction and sustaining of chronic allergic bronchial inflammation, acquiring additional neurogenic features, and to the increase of reactivity in paroxysm-generating neuronal structures, which results in the appearance of the new, secondary trigger factors capable of inducing paroxysm (so called "asthmatization" of the pathologic state (Fuchs E. Bronchial asthma. Sandoz, Berne, 1981)) which is similar to the formation of the new, secondary trigger foci of epileptic activity in epilepsy.
  • This increased asthmatic susceptibility is analogue of the increased seizure susceptibility (predisposition) in epilepsy, and asthmatic status can be considered as a certain analogue of the epileptic status.
  • Attenuation of the trigger, as well as the generator central neurogenic paroxysmal component results in the disappearance of the clinical manifestations of the disease. Very often it is not possible to determine exactly the nature of the trigger factors (especially with their variety), which makes it difficult to influence them by pharmaceutical agents or other methods. Consequently, therapeutic interventions aimed at the paroxysm - generating factors are more justified - e.g. anticonvulsive agents. This class of medication has been successfully applied by us.
  • the possible trigger factors and mechanisms are as follows: allergy and allergic inflammation in respiratory tract, infections of respiratory tract, pathological changes in upper respiratory tract (predominantly in nasopharynx: adenoids, chronic inflammation, etc.) and nasal cavity, physical exercise, hyperventilation, inspiration of dry or cold air, psychogenic factors, intensive smell, inspiration of irritating substances, meteorological factors, allergic processes outside respiratory tract, irritation of interoceptors, endocrine disorders, non-steroidal anti- inflammatory drugs, etc.
  • Trigger factors are , well studied, but exact location of central neurogenic generating structures of bronchial asthma is still unknown, and we do not know, in which limited neuronal populations the increased activity and/or paroxysmal discharges occurs, and which structures of CNS have relationship to this process. It is without doubt that vagus nerve, central and peripheral structures of parasympathetic autonomic nervous system, some structures of brain stem, limbic system, certain areas of hy ⁇ othalamus and the central nervous system structures related to them are involved in this process.
  • efficacy of anticonvulsants in bronchial asthma is due not only to their central effect, but also to the local effect on the airways: reduction of sensitivity of local nerve terminals, local anti-inflammatory effect, especially inhibition of axon reflexes, which are considered by some authors * to be one of the mechanisms of neurogenic inflammation (Rihoux J- P. The allergic reaction. UCB Pharmaceutical Sector - Braine-l'Alleud, Brussels, 1993), inhibition of neuropeptide release from axon terminals in bronchial wall, reduction of peripheral neuromuscular transmission on periphery, local effect on cells membranes and direct relaxing effect on the bronchial smooth muscles and inhibition of post-tetanic depolarization.
  • anticonvulsive agents act similarly to the substances, reducing elevated vagal tonus and tonus of other nerves, and in this way cause bronchodilation and reduction of neurogenic inflammation. It is known, that vagal stimulation in experimental animals results in accentuation of neurogenic inflammation in airways (Morikawa M. Sekizawa K. Sasaki H. Inhibitory actions of cyclic AMP on neurogenic plasma extravasation in rat airways. European Journal of Pharmacology, 241(l):83-7, 1993.
  • anticonvulsants inhibit neuronal discharges of any kind: epileptogenic or non-epileptogenic. This property of anticonvulsants explains their efficacy in variety of non-epileptic conditions (Kryzhanovskii GN. Determinant structures in pathologic conditions of the nervous system. Generator mechanisms of neuropathologic syndromes. [Russian]. AMS USSR, Me ⁇ tsina, Moscow, 1980). It is also possible, that anticonvulsants act via neurogenic control of immune reactions. Neurogenic control of immune reactions was first described at the beginning of the 20th century (Besredka A., Steinhardt E. Du mechanisme de I'antianaphylaxie. [French]. Ann.Inst.
  • Bronchial asthma is not the only disease having pathogenic mechanisms similar to that of epilepsy.
  • Trigeminal neuralgia being the condition of hyperreactivity with paroxysmal clinical manifestations has certain pathogenic similarity with epilepsy (Karlov VA. Poliantsev NA. Petrenko SE. Nilkov NG. Visual evoked potentials in patients with trigeminal neuralgia. [Russian] Zhurn. Nevropatol. i Psikhiatr., 83 (5): 692-6, 1983; Kryzhanovskii GN. Reshetniak VK. Igon'kina SI. Zinkevich VA. [Epileptiform activity in the somatosensory cortex of rats with trigeminal neuralgia].
  • trigeminal neuralgia has a peripheral cause and a central pathogenesis (Fromm GH, Terrence CF, Maroon JC. Trigeminal neuralgia. Current concepts regarding etiology and pathogenesis. Arch. Neurol, 41 : 1204-1207, 1984). Chronic "irritation" of the peripheral trigeminal nerve leads to failure of segmental inhibition in the trigeminal nucleus and to production of ectopic action potentials in the trigeminal nerve.
  • Migraine also has similarity with epilepsy
  • Migraine is a disease of hyperreactivity with paroxysmal clinical manifestation.
  • Several investigators consider that migraine and epilepsy have certain common pathogenic mechanisms (Donnet A Bartolomei F Migraine with visual aura and photosensitive epileptic seizures Epilepsia, 38(9) 1032-4, 1997, Terwindt GM, Ophoff RA, Haan J, Sandkuijl LA, Frants RR, Ferrari MD Migraine, ataxia and epilepsy a challenging spectrum of genetically determined calcium channelopathies Dutch Migraine Genetics Research Group [Review] European Journal of Human Genetics, 6(4) 297-307, 1998) The aura is often observed before the migraine attacks, and migraine status may develop Central structures of the nervous system are involved in pathogenesis of migraine paroxysms (Shtok VN Headache [Russian] Meditsina, Moscow, 1987) Migraine paroxysms can be triggered by auditory and photo stimulus, smells, psychoemotional factors
  • peripheral trigger or humoral level with specific effective groups of medications e.g. non- steroidal anti-inflammatory drugs are effective for the treatment of migraine and trigeminal neuralgia, but at the same time they are contraindicated in bronchial asthma; ⁇ 2-adrenomimetics are effective for bronchial asthma, but ⁇ 2-adrenoblockers - for migraine, and at the same time ⁇ 2-adrenoblockers are contraindicated in bronchial asthma).
  • ⁇ 2-adrenomimetics are effective for bronchial asthma, but ⁇ 2-adrenoblockers - for migraine, and at the same time ⁇ 2-adrenoblockers are contraindicated in bronchial asthma.
  • Use of anticonvulsive medicine valproic acid was started on December 15, 1996. In 6 days the asthmatic attacks stopped, after that the patient during more than five years she takes only antiepileptic agents (valproic acid, lamotrigine, felbamate). During this time the attacks of asthma were not observed with the patient. At present, Peak Expiratory Flow Volume Rate of the patient is within the normal limits. Before the treatment with anticonvulsants the patient did not experience such long period without asthmatic attacks.
  • volume Rate of the patient is within the normal limits Before the treatment with anticonvulsants the patient did not experience such long period without asthmatic attacks

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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Organic Chemistry (AREA)
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Abstract

La présente invention, qui a trait à la médecine, notamment à la pharmacologie et à la pharmacothérapie, vise à prévenir des bronchospasmes expiratoires spécifiques chez des patients souffrant d'asthme bronchique et autres affections ou états pathologiques. Cette indication, fondamentalement nouvelle, concerne l'utilisation d'agents antiépileptiques pour le traitement de tout type d'asthme, d'état de mal asthmatique, de bronchite asthmatique ou allergique, d'hyperréactivité bronchique et de syndrome bronchospasmodique, ainsi que pour le traitement des affections liées à ces syndromes et le traitement de la rhinite allergique ou spasmodique et de la rhinoconjonctivite.
EP00922799A 1999-04-30 2000-04-28 Nouvelle indication pour l'utilisation d'agents et de medicaments antiepileptiques Withdrawn EP1175209A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GE1999003512 1999-04-30
GE99003512 1999-04-30
PCT/GE2000/000002 WO2000066096A2 (fr) 1999-04-30 2000-04-28 Nouvelle indication pour l'utilisation d'agents et de medicaments antiepileptiques

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