WO1999013879A1 - Pharmaceutical compositions containing a monoamine oxydase inhibitor and their use in therapy - Google Patents

Pharmaceutical compositions containing a monoamine oxydase inhibitor and their use in therapy Download PDF

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Publication number
WO1999013879A1
WO1999013879A1 PCT/FR1998/001929 FR9801929W WO9913879A1 WO 1999013879 A1 WO1999013879 A1 WO 1999013879A1 FR 9801929 W FR9801929 W FR 9801929W WO 9913879 A1 WO9913879 A1 WO 9913879A1
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agonist
antagonist
presynaptic
pharmaceutical composition
monoamine oxidase
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PCT/FR1998/001929
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French (fr)
Inventor
Henri Depoortere
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Sanofi-Synthelabo
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Priority to AU90819/98A priority Critical patent/AU9081998A/en
Publication of WO1999013879A1 publication Critical patent/WO1999013879A1/en

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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
    • A61K31/495—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

Definitions

  • the present invention relates to pharmaceutical compositions comprising a monoamine oxidase inhibitor, a presynaptic 5-HT ⁇ antagonist and a 5-H ⁇ i A 'agonist as well as their therapeutic application.
  • One of the current techniques for treating depression is based on increasing central serotonergic neurotransmission through an increase in the concentration of serotonin in the synaptic cleft.
  • This increase in serotonin concentration can be obtained, in particular, by monoamine oxidase inhibitors (MAOIs) and serotonin reuptake inhibitors.
  • monoamine oxidase is involved in the catabolism of serotonin. Its inhibition leads to the accumulation of serotonin in the synaptic cleft, but also in the region of cell bodies, where somatodendritic autoreceptors of the 5-HT jj ⁇ type are located, which control the neuronal activity of serotonergic cells and in large part release of serotonin. Somatodendritic autoreceptors, when activated by a high concentration of serotonin, decrease the frequency of serotonin discharge from serotonergic neurons in the dorsal raphe.
  • the antidepressant activity of a compound can be reflected by its action on REM sleep: increase in the latency time of onset of the first phase of REM sleep and reduction in the total duration of REM sleep.
  • the action on REM sleep of an antidepressant compound is a recognized model, making it possible to assess the therapeutic efficacy of such a compound.
  • this type of association does not make it possible, for a given MAOI, to increase the latency time of onset of the first phase of REM sleep, nor to decrease the total duration of sleep paradoxical, enough. It also does not make it possible to significantly reduce the dose of MAOIs, or even of the presynaptic antagonist ô-HT place, so as to reduce the risks of occurrence of side effects, while preserving therapeutic efficacy.
  • a first object of the invention consists of a pharmaceutical composition comprising at least one MAOI, the therapeutic efficacy of which is considerably increased compared to known compositions comprising this same MAOI.
  • a second subject of the invention consists of a pharmaceutical composition comprising at least one MAOI in an effective dose reduced compared to known compositions comprising this same MAOI.
  • a third subject of the invention consists of a pharmaceutical composition comprising at least one MAOI which makes it possible to obtain a very significant increase in the latency time of onset of the first phase of REM sleep and a reduction in the total duration of REM sleep. , compared to the effects observed with known compositions comprising this same MAOI.
  • the subject of the present invention is therefore a pharmaceutical composition
  • a pharmaceutical composition comprising a monoamine oxidase inhibitor, a presynaptic antagonist 5-HT- ⁇ and an agonist 5-HT 1A as a combination product for simultaneous, separate or spread over time use. treatment of depression.
  • the term “simultaneous use” is understood to mean the administration of the compounds of the composition according to the invention included in one and the same pharmaceutical form.
  • the period of time between the administration of the first compound of the composition according to the invention and the administration of the last compound of the same composition according to the invention does not exceed usually not 24 hours.
  • the composition according to the invention considerably increases the effectiveness of the treatment of depression, for a given MAOI.
  • the therapeutic effect of a given MAOI is unexpectedly potentiated by the administration of a presynaptic 5-HT 1A antagonist and a 5-HT 1A agonist.
  • Another major subsequent advantage produced by a composition according to the invention relates to the possibility of using effective doses of lower active principle, which makes it possible to avoid or reduce the risks of the appearance of effects. side effects, in particular the "tyramine" effect.
  • composition according to the invention makes it possible to achieve the expected therapeutic effect more quickly, by eliminating the delay in the onset of desensitization by the presynaptic 5-HT 1A inhibitor and by enhancing serotonergic transmission by the agonist
  • the MAOI can be a reversible or irreversible MAOI A, a reversible or irreversible MAOI or a reversible or irreversible mixed MAOI.
  • MAOIs mention may be made of the compounds described:
  • reversible MAOI there may be mentioned: befloxatone, moclobé ide, brofaromine, phenoxathine, esuprone, befol, RS 8359 (Sankyo), T794 (Tanabé), KP 9 ( Krenitsky, USA), E 2011 (Eisei), toloxatone, pirlindole, amiflamine, serclore ine, kalinaprine,
  • E 4414 Esteve
  • gepirone ipsapirone
  • LY 293284 Lily
  • AP 521 Asahi
  • AZ 16596 Asahi
  • BMS 184111 Bristol Myers Squibb
  • DDR 203901 Roche
  • DDR 205852 Yamamoto
  • DDR 208978 Asahi Chemical
  • DDR 211278 Bayer
  • DDR 212219 E 4414 (Esteve), gepirone, ipsapirone, LY 293284 (Lilly), AP 521 (Asahi), AZ 16596 ( Asahi), BMS 184111 (Bristol Myers Squibb), DDR 203901 (Roche), DDR 205852 (Yamanouchi), DDR 208978 (Asahi Chemical), DDR 211278 (Bayer), DDR 212219
  • the 5-HT 1A agonist can be either a complete 5-HT 3 agonist or a partial 5-HT 3 agonist with respect to postsynaptic affinity, such as for example buspirone.
  • a selective 5-HT 5 somatodendritic receptor antagonist is preferred, which controls neuronal activity and the release of serotonin from serotonergic neurons.
  • Pindolol in the form of (-) pindolol, (+) pindolol or racemate, is currently the most selective presynaptic antagonist. Pindolol, in all its forms, is therefore very particularly preferred in the context of the present invention.
  • the MAOIs of reversible type A, B or mixed are preferred.
  • Befloxatone is most particularly preferred as an MAOI.
  • Pindolol and buspirone are particularly preferred respectively as an antagonist presynaptic 5-HT 1A and 5-HT 1A agonist.
  • composition according to the invention comprising these three compounds is therefore particularly advantageous.
  • Another subject of the invention consists of a pharmaceutical composition
  • a pharmaceutical composition comprising a monoamine oxidase inhibitor, a 5-HT 3 presynaptic antagonist and a 5-HT 1A agonist.
  • This pharmaceutical composition preferably comprises, as MAOIs, befloxatone, as 5-HT-y ⁇ presynaptic antagonist, pindolol, and as 5-HT1A agonist, buspirone.
  • composition according to the present invention may be presented in any form suitable for oral or parenteral administration such as tablets, dragees, capsules, capsules, suspension or oral or injectable solutions, if necessary, in combination with suitable excipients.
  • oral forms are preferred.
  • these forms are dosed to allow daily administration of:
  • the preferred doses are:
  • a composition according to the invention makes it possible to reduce the dosage to one or more of the compounds which constitute it by a factor of 1 to 5 compared to the conventional dosage of each of these compounds used alone, and this while maintaining therapeutic efficacy.
  • a major advantage of the invention lies in the fact that the doses used in the context of the invention are below the conventional doses for administration as monotherapy. This avoids the side effects linked to each of the constituent compounds of the composition according to the invention.
  • composition according to the invention can be administered in a single daily dose or in divided daily doses. In the latter case, the composition according to the invention can be administered in 2 to 4 doses.
  • the reduction factor can vary between 2 and 5 compared to the conventional dosage in each of these compounds used alone, while maintaining therapeutic efficacy.
  • a composition according to the invention comprising an MAOI, a presynaptic antagonist 5-HT j ⁇ and an agonist 5-H j ⁇ has been the subject of pharmacological studies which have demonstrated an unexpected synergistic effect on REM sleep and therefore a definite interest as an antidepressant.
  • the effects of this composition were analyzed on the study of the sleep-wake cycle in the implanted free rat recorded during the lighting period. This study constitutes a model allowing to evaluate the postsynaptic efficacy and the duration of action of antidepressant products.
  • the rat's daily sleep process has strong similarities to the sleep process of humans and even other mammals.
  • Electroencephalograms (EEG) recorded during sleep are used to test the effects of the various compounds administered, comparative or according to the invention.
  • the sleep-wake cycle of the free rat is subject to a circadian rhythm governed by the lighting conditions. Under very strict recording conditions (light / dark cycle of 12 hours / 12 hours, temperature 22 ⁇ 1 ° C), the sleep-wake cycle, under the control of the "biological clock", follows a very regular rhythm , from one day to another. This stability can be found for partial recordings of the nycthemera provided that they are made at fixed times (Depoortere H. et al., Neuropsychobiology, 16, 157-162, 1986).
  • the lighting is maintained from 7 a.m. to 7 p.m. and the recording, which lasts 6 hours, takes place between 11 a.m. and 5 p.m.
  • 6 electrodes constituted by small stainless steel screws (0.9 mm in diameter) are placed in contact with the dura mater: 2 electrodes (1 per hemisphere) at the level of the sensorimotor cortex ( 2 mm behind the bregma, 3 mm laterally to the median suture), 2 electrodes at the level of the visual cortex (2 mm in front of the lambda and 2 mm laterally) and 2 electrodes at the level of the cerebellar cortex, reference electrode (3 mm laterally to the median plane).
  • the electrodes are connected to a connector (Winchester, 7 contacts) by a silver wire.
  • the electrodes and the connector are made integral with the bone by dental cement (Svedia Lamell resin surround).
  • the rats are connected to the recording system (Grass model 79D) by a flexible cable fitted with a rotating connector (APCL 12-way, air precision).
  • the signal is amplified and filtered (1 to 16 Hz, 48 dB / octave). All the EEG signals are recorded on a magnetic recorder (Data recorder RTP-802 A, Kyowa).
  • EEG signals are digitized (sampling frequency at 70 Hz) on a computer (PC Compaq Deskpro 486/33, Axotape program, Axon instrument). The digitized EEG signal is calculated according to the Hjorth "activity / complexity" parameters per 4-second period over the 6 hours of recording.
  • the rats are placed in plexiglass cylinders (60 cm in diameter) with food and drink ad libitum. Before each experiment, the rats are accustomed to the enclosure for at least 3 days. Each recording lasts 6 hours (from 11 a.m. to 5 p.m.) and each experimental session consists of 3 days: 1 control day (vehicle: physiological serum + 1 drop of Tween 80), 1 "product" day and 1 24-hour control day after the administration of the "product”.
  • 1 control day vehicle: physiological serum + 1 drop of Tween 80
  • product day 1 24-hour control day after the administration of the "product”.
  • the "products" to be studied or the vehicle are administered intraperitoneally (i.p.) 15 minutes before recording.
  • the total duration and hourly analysis of each stage are evaluated as well as the latency of onset of SP.
  • Statistical analysis of the results is carried out using Student's "t" test for paired series (Depoortere H. et al., Neuropsychobi ology, 32, 214-221, 1995; Depoortere H. et al., Pharmacol. Biochem. Behav., 51 (4), 571-576, 1995).
  • triple therapy (according to the invention):
  • the appendix presents, in the form of histograms, the results relating to REM sleep, averaged over all of the rats studied, hour by hour during the first 6 hours of the experimental session described above. This representation makes it possible in particular to view the duration of action, defined below.
  • duration of action is understood here to mean the duration, expressed in hours, during which a statistically significant decrease is observed (p “0.05 or p“ 0.01, distinguished respectively by * and ** in the table and l 'appendix) or a disappearance of REM sleep compared to the control records (vehicle administration only).
  • composition according to the invention shows the power of a composition according to the invention as a new treatment for various forms of depression, for example major depression, dysthimia, manic-depressive psychosis, etc.
  • a very effective composition is obtained on the sleep-wake states, and in particular at the level of MS, an increase in the time of appearance and a reduction in the total duration of MS.
  • the synergy phenomenon makes it possible to administer lower doses of MAOIs and thus avoids the side effects, in particular the tyramine effect, while maintaining a therapeutic efficacy.
  • This treatment also allows an overall improvement in the quality of sleep. Indeed, the increase in the total duration of wakefulness, provoked by the administration of the composition according to the invention can also accentuate the "process S", (Borbely AA, Experimental Brain Research, Suppl. 8, Springer- Verlag Berlin, Heidelberg, 1984) reduced in depressed people. In fact, the slow rhythms and duration of deep sleep are not altered after the initial phase of arousal, while the SP continues to be reduced.
  • the strengthening of postsynaptic serotonergic transmission, responsible in particular for the reduction of REM sleep, and the blocking of serotoninergic autoreceptors should make it possible to reduce the time of onset of the therapeutic effect.
  • the absence of rebound phenomenon 24 hours after treatment suggests a good tolerance and the absence of tachyphylaxis during prolonged treatment.
  • composition confers an anxiolytic activity in particular due to the presence of a 5-HT 3 agonist of the buspirone type
  • composition makes it possible to influence the chronobiology in particular by means of the ⁇ -blocking antagonistic properties of the pindolol type.
  • the pharmaceutical composition according to the invention can also be used for the treatment of generalized anxiety, social phobias, panic attacks, cognitive disorders, psychoses, sleep disorders and obsessive-compulsive disorders.
  • SP% variation of the total duration of the SP in% compared to the Lat control SP min: variation of the latency time in min compared to the Ev control. %: variation of the duration of wakefulness in% compared to the control

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Abstract

The invention concerns pharmaceutical compositions containing a monoamine oxydase inhibitor, a 5-HT1A presynaptic antagonist and a 5-HT1A agonist as combination product to be used simultaneously, separately or spread over time for treating different forms of depression.

Description

COMPOSITIONS PHARMACEUTIQUES CONTENANT UN INHIBITEUR DE LA MONOAMINE OXYDASE ET LEUR APPLICATION EN THERAPEUTIQUEPHARMACEUTICAL COMPOSITIONS CONTAINING A MONOAMINE OXIDASE INHIBITOR AND THEIR THERAPEUTIC APPLICATION
La présente invention a pour objet des compositions pharmaceutiques comprenant un inhibiteur de la monoamine oxydase, un antagoniste présynaptique 5-HT^ et un agoniste 5-HτiA' ainsi que leur application en thérapeutique.The present invention relates to pharmaceutical compositions comprising a monoamine oxidase inhibitor, a presynaptic 5-HT ^ antagonist and a 5-Hτ i A 'agonist as well as their therapeutic application.
L'une des techniques actuelles de traitement de la dépression repose sur l'augmentation de la neurotransmission serotoninergique centrale par le biais d'une augmentation de la concentration de la sérotonine dans la fente synaptique. Cette augmentation de la concentration en sérotonine peut être obtenue, notamment, par les inhibiteurs de la monoamine oxydase (IMAO) et les inhibiteurs de la recapture de la sérotonine.One of the current techniques for treating depression is based on increasing central serotonergic neurotransmission through an increase in the concentration of serotonin in the synaptic cleft. This increase in serotonin concentration can be obtained, in particular, by monoamine oxidase inhibitors (MAOIs) and serotonin reuptake inhibitors.
Plus spécifiquement, la monoamine oxydase est impliquée dans le catabolisme de la sérotonine. Son inhibition entraîne l'accumulation de la sérotonine dans la fente synaptique, mais aussi dans la région des corps cellulaires, où sont localisés les autorécepteurs somatodendritiques du type 5-HTjj^, qui contrôlent l'activité neuronale des cellules sérotoninergiques et en grande partie la libération de sérotonine. Les autorécepteurs somatodendritiques, lorsqu'ils sont activés par une concentration élevée de sérotonine, diminuent la fréquence de décharge en sérotonine des neurones sérotoninergiques du raphé dorsal. Puis, cet effet de diminution de fréquence de décharge s'estompe car les autorécepteurs somatodendritiques du type 5-HT^ se désensibilisent, permettant ainsi un rétablissement de la libération de sérotonine dans les régions postsynaptiques. La restauration des décharges des cellules sérotoninergiques apparaît après quelques semaines de traitement, coïncidant avec l'apparition des effets cliniques (Blier P. et al., J. Clin . Psychiatry, 51, 14-20, 1990) . Un désavantage du traitement par les antidépresseurs en général (par exemple : les inhibiteurs de la recapture de la noradrénaline, de la sérotonine, et de la dopamine ; les IMAO), réside donc dans l'apparition tardive de l'effet thérapeutique (délai moyen de 3 semaines) . En outre, les doses d' IMAO nécessaires pour observer un effet thérapeutique sont telles qu'elles peuvent favoriser l'apparition d'effets secondaires tels que l'effet "tyramine" (cheese effect) . On peut citer d'autres effets secondaires reconnus, parmi lesquels : insomnie, hypotension orthostatique, dysfonctionnement sexuel, en particulier impuissance, hypomanie et interactions médicamenteuses (Remick R.A. et al., Prog. Neuropsychopharmacol . Biol . Psychia try, 13, 497-504,1989) . Le lien entre la neurotransmission serotoninergique et la régulation du sommeil paradoxal a été décrite dans Adrien J., Je sommeil normal et pathologique, M. Billard. Masson, Paris, 27-38, 1994 et dans Stériade M. et al., Brainstem control of wakefulness and sleep, Stériade and Me Carley, Plénum Press, New York, 363-393, 1990. C'est ainsi que lors de l'état dépressif, dont le dysfonctionnement se traduit notamment par une baisse des neurotransmissions monoaminergiques, on observe une apparition précoce de la première phase de sommeil paradoxal, dont la durée a tendance à être prolongée. D'autres troubles du sommeil surviennent chez le sujet dépressif tels que l'augmentation du nombre d'éveils et la réduction du temps de sommeil total : on observe une altération globale du sommeil (Reynolds III Ch.F. et al., Sleep, 10(3), 199-215, 1987 ; Kerkhofs M., le sommeil normal et pa thologique, M. Billard. Masson, Paris, 487-506, 1994) . A l'inverse, il est connu que l'augmentation de la neurotransmission serotoninergique est responsable de l'inhibition du sommeil paradoxal. L'activité antidépressive d'un composé peut se refléter par son action sur le sommeil paradoxal : augmentation du temps de latence d'apparition de la première phase du sommeil paradoxal et réduction de la durée totale de sommeil paradoxal. L'action sur le sommeil paradoxal d'un composé antidépresseur est un modèle reconnu, permettant d'apprécier l'efficacité thérapeutique d'un tel composé.More specifically, monoamine oxidase is involved in the catabolism of serotonin. Its inhibition leads to the accumulation of serotonin in the synaptic cleft, but also in the region of cell bodies, where somatodendritic autoreceptors of the 5-HT jj ^ type are located, which control the neuronal activity of serotonergic cells and in large part release of serotonin. Somatodendritic autoreceptors, when activated by a high concentration of serotonin, decrease the frequency of serotonin discharge from serotonergic neurons in the dorsal raphe. Then, this effect of decreasing the frequency of discharge fades because the somatodendritic autoreceptors of the 5-HT ^ type become desensitized, thus allowing a re-establishment of the release of serotonin in the postsynaptic regions. Restoration of the discharges of serotonergic cells appears after a few weeks of treatment, coinciding with the appearance of clinical effects (Blier P. et al., J. Clin. Psychiatry, 51, 14-20, 1990). A disadvantage of treatment with antidepressants in general (for example: norepinephrine, serotonin, and dopamine reuptake inhibitors; MAOIs) therefore lies in the late onset of the therapeutic effect (average time 3 weeks). In addition, doses of MAOIs necessary to observe a therapeutic effect are such that they can favor the appearance of side effects such as the "tyramine" effect (cheese effect). We can cite other recognized side effects, among which: insomnia, orthostatic hypotension, sexual dysfunction, in particular impotence, hypomania and drug interactions (Remick RA et al., Prog. Neuropsychopharmacol. Biol. Psychia try, 13, 497-504 , 1989). The link between serotonergic neurotransmission and the regulation of REM sleep has been described in Adrien J., I normal and pathological sleep, M. Billard. Masson, Paris, 27-38, 1994 and in Stériade M. et al., Brainstem control of wakefulness and sleep, Stériade and Me Carley, Plénum Press, New York, 363-393, 1990. This is how during the he depressive state, the dysfunction of which is reflected in particular by a decrease in monoaminergic neurotransmissions, there is an early onset of the first phase of REM sleep, the duration of which tends to be prolonged. Other sleep disorders occur in the depressed subject such as the increase in the number of awakenings and the reduction of the total sleep time: we observe an overall alteration of sleep (Reynolds III Ch.F. et al., Sleep, 10 (3), 199-215, 1987; Kerkhofs M., normal sleep and pathology, M. Billard. Masson, Paris, 487-506, 1994). Conversely, it is known that the increase in serotonergic neurotransmission is responsible for the inhibition of REM sleep. The antidepressant activity of a compound can be reflected by its action on REM sleep: increase in the latency time of onset of the first phase of REM sleep and reduction in the total duration of REM sleep. The action on REM sleep of an antidepressant compound is a recognized model, making it possible to assess the therapeutic efficacy of such a compound.
Il a été rapporté que le traitement par un antagoniste 5-HT^ en association avec soit un inhibiteur sélectif de la recapture de la sérotonine soit un IMAO pouvait augmenter l'efficacité du traitement antidépressif chez les déprimés et raccourcir le délai d'apparition de l'effet antidépresseur (Artigas F. et al., Arch . Gen . Psychiatry, 51, 248-251, 1994 ; Blier P. et al., J. Clin . Psychopharmacol . , 15, 217-222, 1995) .Treatment with a 5-HT ^ antagonist in combination with either a selective serotonin reuptake inhibitor or an MAOI has been reported to increase the effectiveness of antidepressant therapy in the depressed and shorten the time of onset of the antidepressant effect (Artigas F. et al., Arch. Gen. Psychiatry, 51, 248-251, 1994; Blier P. et al., J. Clin. Psychopharmacol., 15, 217 -222, 1995).
Mais, comme la demanderesse a pu le constater, ce type d'association ne permet pas, pour un IMAO donné, d'augmenter le temps de latence d'apparition de la première phase de sommeil paradoxal, ni de diminuer la durée totale de sommeil paradoxal, de manière suffisante. Elle ne permet pas non plus de diminuer de façon conséquente la dose en IMAO, voire en antagoniste présynaptique ô-HT^, de sorte à diminuer les risques d'apparition des effets secondaires, tout en préservant une efficacité thérapeutique.But, as the Applicant has been able to observe, this type of association does not make it possible, for a given MAOI, to increase the latency time of onset of the first phase of REM sleep, nor to decrease the total duration of sleep paradoxical, enough. It also does not make it possible to significantly reduce the dose of MAOIs, or even of the presynaptic antagonist ô-HT sorte, so as to reduce the risks of occurrence of side effects, while preserving therapeutic efficacy.
Un premier objet de l'invention consiste en une composition pharmaceutique comprenant au moins un IMAO, dont l'efficacité thérapeutique est considérablement accrue par rapport aux compositions connues comprenant ce même IMAO. Un deuxième objet de l'invention consiste en une composition pharmaceutique comprenant au moins un IMAO en une dose efficace réduite par rapport aux compositions connues comprenant ce même IMAO.A first object of the invention consists of a pharmaceutical composition comprising at least one MAOI, the therapeutic efficacy of which is considerably increased compared to known compositions comprising this same MAOI. A second subject of the invention consists of a pharmaceutical composition comprising at least one MAOI in an effective dose reduced compared to known compositions comprising this same MAOI.
Un troisième objet de l'invention consiste en une composition pharmaceutique comprenant au moins un IMAO qui permet d'obtenir une augmentation très significative du temps de latence d'apparition de la première phase de sommeil paradoxal et une diminution de la durée totale de sommeil paradoxal, par rapport aux effets observés avec des compositions connues comprenant ce même IMAO.A third subject of the invention consists of a pharmaceutical composition comprising at least one MAOI which makes it possible to obtain a very significant increase in the latency time of onset of the first phase of REM sleep and a reduction in the total duration of REM sleep. , compared to the effects observed with known compositions comprising this same MAOI.
La présente invention a alors pour objet une composition pharmaceutique comprenant un inhibiteur de la monoamine oxydase, un antagoniste présynaptique 5-HT-^ et un agoniste 5-HT1A comme produit de combinaison pour une utilisation simultanée, séparée ou étalée dans le temps pour le traitement de la dépression. On entend par "utilisation simultanée" l'administration des composés de la composition selon l'invention compris dans une seule et même forme pharmaceutique.The subject of the present invention is therefore a pharmaceutical composition comprising a monoamine oxidase inhibitor, a presynaptic antagonist 5-HT- ^ and an agonist 5-HT 1A as a combination product for simultaneous, separate or spread over time use. treatment of depression. The term “simultaneous use” is understood to mean the administration of the compounds of the composition according to the invention included in one and the same pharmaceutical form.
On entend par "utilisation séparée" : - l'administration, en même temps, de deux des composés de la composition selon l'invention, compris dans une seule et même forme pharmaceutique et du composé de la composition restant, compris dans une forme pharmaceutique distincte ou,The term "separate use" means: the administration, at the same time, of two of the compounds of the composition according to the invention, included in one and the same pharmaceutical form and of the compound of the remaining composition, included in a pharmaceutical form separate or,
- l'administration, en même temps, des trois composés de la composition selon l'invention compris dans des formes pharmaceutiques distinctes.the administration, at the same time, of the three compounds of the composition according to the invention included in separate pharmaceutical forms.
On entend par "utilisation étalée dans le temps" :"Spread over time" means:
- l'administration successive, d'une part, en même temps, de deux des composés de la composition selon l'invention, compris dans des formes pharmaceutiques distinctes ou dans une seule et même forme pharmaceutique, et d'autre part, du composé de la composition selon l'invention restant, compris dans une forme pharmaceutique propre ou,the successive administration, on the one hand, at the same time, of two of the compounds of the composition according to the invention, included in separate pharmaceutical forms or in one and the same pharmaceutical form, and on the other hand, of the compound of the composition according to the invention remaining, included in a clean pharmaceutical form or,
- l'administration successive des composés de la composition selon l'invention, compris chacun dans une forme pharmaceutique distincte.the successive administration of the compounds of the composition according to the invention, each included in a separate pharmaceutical form.
Dans le cas de cette "utilisation étalée dans le temps", le laps de temps écoulé entre l'administration du premier composé de la composition selon l'invention et l'administration du dernier composé de la même composition selon l'invention n'excède généralement pas 24 heures.In the case of this "use spread over time", the period of time between the administration of the first compound of the composition according to the invention and the administration of the last compound of the same composition according to the invention does not exceed usually not 24 hours.
D'une façon générale, la composition selon l'invention augmente considérablement l'efficacité du traitement de la dépression, pour un IMAO donné. En d'autres termes, l'effet thérapeutique d'un IMAO donné est potentialisé de manière inattendue par l'administration d'un antagoniste présynaptique 5-HT1A et d'un agoniste 5-HT1A. Un autre avantage subséquent majeur produit par une composition selon l'invention, concerne la possibilité d'utiliser des doses efficaces en principe actif plus faibles, ce qui permet d'éviter ou de réduire les risques d'apparition des effets secondaires, en particulier l'effet "tyramine". De plus, cette composition selon l'invention permet d'atteindre l'effet thérapeutique escompté plus rapidement, en éliminant le délai d'apparition de la désensibilisation par l'inhibiteur 5-HT1A présynaptique et en renforçant la transmission serotoninergique par l' agoniste 5-HT^.In general, the composition according to the invention considerably increases the effectiveness of the treatment of depression, for a given MAOI. In other words, the therapeutic effect of a given MAOI is unexpectedly potentiated by the administration of a presynaptic 5-HT 1A antagonist and a 5-HT 1A agonist. Another major subsequent advantage produced by a composition according to the invention relates to the possibility of using effective doses of lower active principle, which makes it possible to avoid or reduce the risks of the appearance of effects. side effects, in particular the "tyramine" effect. In addition, this composition according to the invention makes it possible to achieve the expected therapeutic effect more quickly, by eliminating the delay in the onset of desensitization by the presynaptic 5-HT 1A inhibitor and by enhancing serotonergic transmission by the agonist. 5-HT ^.
Dans le cadre de l'invention, l'IMAO peut être un IMAO A réversible ou irréversible, un IMAO B réversible ou irréversible ou un IMAO mixte réversible ou irréversible. A titre d' IMAO on peut citer les composés décrits :In the context of the invention, the MAOI can be a reversible or irreversible MAOI A, a reversible or irreversible MAOI or a reversible or irreversible mixed MAOI. As MAOIs, mention may be made of the compounds described:
- dans la demande de brevet WO 96/38444, c'est à dire des dérivés d'oxazolidin-2-one, et plus particulièrement la (S) -5-méthoxyméthyl-3- [6- (4, 4, 4-trifluorobutoxy) -1,2- benzisoxazol-3-yl] oxazolidin-2-one,- In patent application WO 96/38444, that is to say derivatives of oxazolidin-2-one, and more particularly (S) -5-methoxymethyl-3- [6- (4, 4, 4- trifluorobutoxy) -1,2- benzisoxazol-3-yl] oxazolidin-2-one,
- dans la demande de brevet EP 0 699 680, c'est à dire des dérivés de 3, 3a, 4, 5-tétrahydro-lH-oxazolo [3, 4-a] quinoléin- 1-one et plus particulièrement la 3-méthoxyméthyl-7- (4, , 4- trifluoro-3-hydroxybutoxy) -3, 3a, 4, 5-tétrahydro-lH- oxazolo [3, 4-a] quinoléin-1-one, la 3-méthoxyméthyl-7- [4, 4, 4- trifluorobutoxy] -3, 3a, 4, 5-tétrahydro-lH- oxazolo [3, 4-a] quinoléine-1-one, la 7- (4,4,4- trifluorobutoxy) ] -3, 3a, 4, 5-tétrahydro-lH-oxazolo [3, 4- a] quinoléine-1-one, la 7- (3-hydroxy-4, 4, 4- trifluorobutoxy) ] -3, 3a, 4, 5-tétrahydro-lif-oxazolo [3, 4- a] quinoléine-1-one, la 3-méthoxyméthyl-7- [ (2- (1- hydroxycyclopentyl) éthoxy] -3, 3a, 4, 5-tétrahydro-lH- oxazolo [3, 4-a] quinoléine-1-one,- In patent application EP 0 699 680, that is to say derivatives of 3, 3a, 4, 5-tetrahydro-1H-oxazolo [3, 4-a] quinoline-1-one and more particularly 3- methoxymethyl-7- (4, 4-trifluoro-3-hydroxybutoxy) -3, 3a, 4, 5-tetrahydro-1H-oxazolo [3, 4-a] quinoline-1-one, 3-methoxymethyl-7- [4, 4, 4 trifluorobutoxy] -3, 3a, 4, 5-tetrahydro-1H-oxazolo [3, 4-a] quinoline-1-one, la 7- (4,4,4- trifluorobutoxy)] - 3, 3a, 4, 5-tetrahydro-1H-oxazolo [3, 4- a] quinoline-1-one, la 7- (3-hydroxy-4, 4, 4 trifluorobutoxy)] -3, 3a, 4, 5-tetrahydro-lif-oxazolo [3, 4- a] quinoline-1-one, 3-methoxymethyl-7- [(2- (1- hydroxycyclopentyl) ethoxy] -3, 3a, 4, 5-tetrahydro-1H - oxazolo [3, 4-a] quinoline-1-one,
- dans la demande de brevet FR 2737206, c'est à dire des dérivés de 3-méthoxyméthyl-3, 3a, 4, 5-tétrahydro-l#- oxazolo [3, 4-a] quinoléin-1-one,- in patent application FR 2737206, that is to say derivatives of 3-methoxymethyl-3, 3a, 4, 5-tetrahydro-l # - oxazolo [3, 4-a] quinoline-1-one,
- dans la demande de brevet WO 97/13768, c'est à dire des dérivés d'oxazolidin-2-one, et plus particulièrement la (R) -5- (méthoxyméthyl) -3- [6- (phénylméthoxy)benzofuran- 3-yl]oxazolidin-2-one, la (R) -5- (méthoxyméthyl) -3- [6- (4, 4, 4- trifluorobutoxy) benzofuran-3-yl ] oxazolidin-2-one, la (R,R) -5- (méthoxyméthyl) -3- [6- (4, 4, 4-trifluoro-3- hydroxybutoxy) benzofuran-3-yl] oxazolidin-2-one, la (R,R) -5- (hydroxyméthyl) -3- [6- (4, 4, 4-trifluoro-3- hydroxybutoxy) benzofuran-3-yl] oxazolidin-2-one, la (R) -5- (méthoxyméthyl) -3- [6- (5, 5, 5-trifluoropentyl) benzofuran- 3-yl]oxazolidin-2-one, la (R) -5- (méthoxyméthyl) -3- [6- (5, 5, 5- trifluoro-4-hydroxypent-l-ènyl)benzofuran-3-yl]oxazolidin-2- one, la (R) -5- (méthoxyméthyl) -3- [6-- In patent application WO 97/13768, that is to say derivatives of oxazolidin-2-one, and more particularly (R) -5- (methoxymethyl) -3- [6- (phenylmethoxy) benzofuran- 3-yl] oxazolidin-2-one, la (R) -5- (methoxymethyl) -3- [6- (4, 4, 4 trifluorobutoxy) benzofuran-3-yl] oxazolidin-2-one, la (R , R) -5- (methoxymethyl) -3- [6- (4, 4, 4-trifluoro-3-hydroxybutoxy) benzofuran-3-yl] oxazolidin-2-one, la (R, R) -5- ( hydroxymethyl) -3- [6- (4, 4, 4-trifluoro-3- hydroxybutoxy) benzofuran-3-yl] oxazolidin-2-one, (R) -5- (methoxymethyl) -3- [6- (5, 5, 5-trifluoropentyl) benzofuran- 3-yl] oxazolidin-2-one , (R) -5- (methoxymethyl) -3- [6- (5, 5, 5- trifluoro-4-hydroxypent-1-enyl) benzofuran-3-yl] oxazolidin-2- one, la (R) -5- (methoxymethyl) -3- [6-
(phénylméthoxy) benzo [b] thién-3-yl] oxazolidin-2-one,(phenylmethoxy) benzo [b] thien-3-yl] oxazolidin-2-one,
- dans la demande de brevet WO 97/17347, c'est à dire des composés dérivés d'oxazolidin-2-one, et plus particulièrement la 3- [2- (3, 3, 3-trifluoropropyl) -3, 4-dihydro- 2H-l-benzopyran- 6-yl ] -5-méthoxyméthyloxazolidin-2-one, la 3- [2-propyl-3, 4-dihydro-2#-l-benzopyran-6-yl] -5- méthoxyméthyloxazolidin-2-one et la 3- [2- (3,3, 3- trifluoropropyl) -2, 3-dihydrobenzofuran-5-yl] -5- méthoxyméthyloxazolidin-2-one, - dans la demande de brevet WO 97/17346, c'est à dire des composés dérivés de 3- (benzofuran-5-yl) oxazolidin-2-one, et plus particulièrement la 3- [2- (3,3,3- trifluoropropyl) benzofuran-5-yl] -5-méthoxyméthyloxazolidin-2- one, la 3- (2-propylbenzofuran-5-yl) -5- méthoxyméthyloxazolidin-2-one, la 3- (2-phénylbenzofuran-5- yl) -5-méthoxyméthyloxazolidin-2-one,- In patent application WO 97/17347, that is to say compounds derived from oxazolidin-2-one, and more particularly 3- [2- (3, 3, 3-trifluoropropyl) -3, 4- dihydro- 2H-1-benzopyran- 6-yl] -5-methoxymethyloxazolidin-2-one, 3- [2-propyl-3, 4-dihydro-2 # -l-benzopyran-6-yl] -5- methoxymethyloxazolidin -2-one and 3- [2- (3,3, 3-trifluoropropyl) -2, 3-dihydrobenzofuran-5-yl] -5- methoxymethyloxazolidin-2-one, - in patent application WO 97/17346 , ie compounds derived from 3- (benzofuran-5-yl) oxazolidin-2-one, and more particularly 3- [2- (3,3,3-trifluoropropyl) benzofuran-5-yl] - 5-methoxymethyloxazolidin-2- one, 3- (2-propylbenzofuran-5-yl) -5- methoxymethyloxazolidin-2-one, 3- (2-phenylbenzofuran-5-yl) -5-methoxymethyloxazolidin-2-one,
- dans la demande de brevet EP 0 655 445, c'est à dire des dérivés de 1, 3, 4-oxadiazol-2 ( 3 H) -one, et plus particulièrement la 5- [4- (4, 4, 4-trifluorobutoxy) phényl] - 3- (2-méthoxyéthyl)-l,3,4-oxadiazol-2 (3H)-one, la 5- [4- (4, 4, 4- trifluorobutoxy) phényl] -3- (2-hydroxyéthyl) -1,3, 4-oxadiazol- 2(3tf)-one, la 5- [4- (4, 4, 4-trifluorobutoxy) phényl] -3- (2- méthylthioéthyl)-l,3,4-oxadiazol-2 (3H)-one, la 5- [4- (4,4, 4- trifluoro-2-butènyloxy) phényl] -3- (2-méthoxyéthyl) -1, 3, 4- oxadiazol-2 (3tf)-one, la 5- [4- (4, 4, 4-trifluoro-3 {R) - hydroxybutoxy) phényl] -3- (2-méthoxyéthyl) -1,3, 4-oxadiazol- 2(3H)-one, la 5- [4- (tétrahydropyran-3-ylméthoxy) phényl] - 3- (2-méthoxyéthyl) -1, 3, 4-oxadiazol-2 ( 3H) -one, tous les composés des différents brevets ou demandes de brevet citées ci-dessus, pouvant être sous forme d' énantiomères, de diastéréoisomères purs ou sous forme de mélanges, y compris de mélange racémique.- In patent application EP 0 655 445, that is to say derivatives of 1, 3, 4-oxadiazol-2 (3 H) -one, and more particularly 5- [4- (4, 4, 4 -trifluorobutoxy) phenyl] - 3- (2-methoxyethyl) -1,3,4-oxadiazol-2 (3H) -one, la 5- [4- (4, 4, 4-trifluorobutoxy) phenyl] -3- ( 2-hydroxyethyl) -1,3,4-oxadiazol- 2 (3tf) -one, la 5- [4- (4, 4, 4-trifluorobutoxy) phenyl] -3- (2-methylthioethyl) -1,3 4-oxadiazol-2 (3H) -one, la 5- [4- (4,4, 4-trifluoro-2-butenyloxy) phenyl] -3- (2-methoxyethyl) -1, 3, 4-oxadiazol-2 (3tf) -one, la 5- [4- (4, 4, 4-trifluoro-3 {R) - hydroxybutoxy) phenyl] -3- (2-methoxyethyl) -1,3, 4-oxadiazol- 2 (3H ) -one, 5- [4- (tetrahydropyran-3-ylmethoxy) phenyl] - 3- (2-methoxyethyl) -1, 3, 4-oxadiazol-2 (3H) -one, all the compounds of the various patents or Patent applications cited above, which may be in the form of enantiomers, pure diastereoisomers or in the form of mixtures, including a racemic mixture.
- dans les brevets ou demandes de brevet suivants : WO 96/39405, US 5494908, WO 96/06837, WO 96/24349, EP 0 670 313, EP 0 504 574, EP 0 363 796, EP 0 363 793, EP O 657 440.- in the following patents or patent applications: WO 96/39405, US 5494908, WO 96/06837, WO 96/24349, EP 0 670 313, EP 0 504 574, EP 0 363 796, EP 0 363 793, EP O 657 440.
Plus particulièrement à titre d' IMAO A réversible on peut citer : la béfloxatone, le moclobé ide, la brofaromine, la phénoxathine, l'esuprone, le befol, le RS 8359 (Sankyo), le T794 (Tanabé), le KP 9 (Krenitsky, USA), le E 2011 (Eisei), la toloxatone, le pirlindole, l' amiflamine, la serclore ine, la bazinaprine,More particularly, as reversible MAOI, there may be mentioned: befloxatone, moclobé ide, brofaromine, phenoxathine, esuprone, befol, RS 8359 (Sankyo), T794 (Tanabé), KP 9 ( Krenitsky, USA), E 2011 (Eisei), toloxatone, pirlindole, amiflamine, serclore ine, bazinaprine,
A titre d' IMAO A irréversibles on peut citer : la clorgyline, le tetrindole,As irreversible MAOIs there may be mentioned: clorgyline, tetrindole,
A titre d' IMAO B réversibles on peut citer : le lazabemide, le milacémide, la caroxazone, l'IFO,As reversible MAOIs there may be mentioned: lazabemide, milacemide, caroxazone, IFO,
A titre d' IMAO B irréversibles on peut citer : le L-deprényl, la mofégiline, la rasagéline, la pargyline, A titre d' IMAO mixtes irréversibles on peut citer : la phénelzine, le nialamide, le tranylcypromine, l' iproniazid, l' isocarboxide.As irreversible MAOIs there may be mentioned: L-deprenyl, mofegilin, rasagelin, pargyline, As irreversible mixed MAOIs one can cite: phenelzine, nialamide, tranylcypromine, iproniazid, l 'isocarboxide.
A titre d' agoniste 5-HT1A, on peut notamment citer les composés suivants : le E 4414 (Esteve) , la gepirone, l'ipsapirone, le LY 293284 (Lilly), le AP 521 (Asahi), le AZ 16596 (Asahi), le BMS 184111 (Bristol Myers Squibb), le DDR 203901 (Roche), le DDR 205852 (Yamanouchi) , le DDR 208978 (Asahi Chemical), le DDR 211278 (Bayer), le DDR 212219As 5-HT 1A agonist, the following compounds may be mentioned: E 4414 (Esteve), gepirone, ipsapirone, LY 293284 (Lilly), AP 521 (Asahi), AZ 16596 ( Asahi), BMS 184111 (Bristol Myers Squibb), DDR 203901 (Roche), DDR 205852 (Yamanouchi), DDR 208978 (Asahi Chemical), DDR 211278 (Bayer), DDR 212219
(Lundbeck) , le F 12439 (P Fabre) , le FCE 23892 (Farmitalia) , le L 0068 / F 11440 (P Fabre), le LY 274600 / LY 274601 (Lilly), le LY 301317 (Lilly), le LY 297996 (Lilly), le NAD 299 (Astra) , le composé référencé sous le n° 3828 dans la base de données Pharamprojects (Lilly), le composé référencé sous le n° 4040 dans la base de données Pharmaprojects (Lundbeck) , le composé référencé sous le n° 4827 dans la base de données Pharmaprojects (Medinnova) , le S 14671 (Servier) , le S 215521 (Servier), le U 92016A (Upjohn), le WAY 100802 (AHP / Wyeth Ayerst), le WY 48723 (Wyeth Ayerst), l'ebalzotan / NAE 086 (Astra), le S 15535 (Servier), l'EMD 67478 (E Merck), , l'alnespirone / S 20499 (Servier), le BAYx 3702 (Bayer), le lesopitron (Esteve Boots), la zalospirone, le flesinoxan, la tandospirone, le CP 110330 / CP 119333 (Pfizer), le EMD 77697 (E Merck), le LY 315535 (Lilly / Roberts), le OPC 14523 (Otsuka), le composé référencé sous le n° 4375 dans la base de données Pharmaprojects (Solvay) , le BIMT 17 / flibanserin (Boehringer Ingelheim) , la binospirone, l'EM 56551 (E Merck), l' adatanserine / WY 50324 (AHP /(Lundbeck), F 12439 (P Fabre), FCE 23892 (Farmitalia), L 0068 / F 11440 (P Fabre), LY 274600 / LY 274601 (Lilly), LY 301317 (Lilly), LY 297996 (Lilly), NAD 299 (Astra), the compound referenced under No. 3828 in the Pharamprojects database (Lilly), the compound referenced under No. 4040 in the Pharmaprojects database (Lundbeck), the compound referenced under No. 4827 in the Pharmaprojects (Medinnova) database, S 14671 (Servier), S 215521 (Servier), U 92016A (Upjohn), WAY 100802 (AHP / Wyeth Ayerst), WY 48723 ( Wyeth Ayerst), ebalzotan / NAE 086 (Astra), S 15535 (Servier), EMD 67478 (E Merck),, alnespirone / S 20499 (Servier), BAYx 3702 (Bayer), lesopitron (Esteve Boots), zalospirone, flesinoxan, tandospirone, CP 110330 / CP 119333 (Pfizer), EMD 77697 (E Merck), LY 315535 (Lilly / Roberts), OPC 14523 (Otsuka), the compound referenced under No. 4375 in the Pharmaprojects database (Solvay), BIMT 17 / flibanserin (Boehringer Ingelheim), binospirone, EM 56551 (E Merck), adatanserin / WY 50324 (AHP /
Weyth-Ayerst) , le BMS 181101 (Bristol Myers Squibb), l'EMD 68843 (E Merck), le piricapiron, le SR 57746 (Sanofi), la bromerguride, le FG 5865 (Kabi Pharmacia), le GR 103691Weyth-Ayerst), BMS 181101 (Bristol Myers Squibb), EMD 68843 (E Merck), piricapiron, SR 57746 (Sanofi), bromerguride, FG 5865 (Kabi Pharmacia), GR 103691
(Glaxo Wellcome), le HT 90 B (Chugai) ou, de préférence, la buspirone.(Glaxo Wellcome), HT 90 B (Chugai) or, preferably, buspirone.
L' agoniste 5-HT1A peut être soit agoniste 5-HT^ complet, soit un agoniste 5-HT^ partiel, vis-à-vis de l'affinité postsynaptique, comme par exemple la buspirone.The 5-HT 1A agonist can be either a complete 5-HT 3 agonist or a partial 5-HT 3 agonist with respect to postsynaptic affinity, such as for example buspirone.
A titre d'antagoniste présynaptique 5-HT1A on préfère un antagoniste sélectif des autorécepteurs 5-HT^ somatodendritique, qui contrôle l'activité neuronale et la libération de sérotonine des neurones sérotoninergiques. Le pindolol, sous forme de (-)pindolol, (+)pindolol ou de racémate, est actuellement l'antagoniste présynaptique le plus sélectif. Le pindolol, sous toutes ses formes, est donc tout particulièrement préféré dans le cadre de la présente invention.As a 5-HT 1A presynaptic antagonist, a selective 5-HT 5 somatodendritic receptor antagonist is preferred, which controls neuronal activity and the release of serotonin from serotonergic neurons. Pindolol, in the form of (-) pindolol, (+) pindolol or racemate, is currently the most selective presynaptic antagonist. Pindolol, in all its forms, is therefore very particularly preferred in the context of the present invention.
Dans le cadre de l'invention, on préfère les IMAO de type réversible A, B ou mixte.In the context of the invention, the MAOIs of reversible type A, B or mixed are preferred.
La béfloxatone est tout particulièrement préférée à titre d'IMAO. Le pindolol et la buspirone sont particulièrement préférés, respectivement en tant qu'antagoniste présynaptique 5-HT1A et agoniste 5-HT1A.Befloxatone is most particularly preferred as an MAOI. Pindolol and buspirone are particularly preferred respectively as an antagonist presynaptic 5-HT 1A and 5-HT 1A agonist.
Une composition selon l'invention comprenant ces trois composés est donc particulièrement avantageuse.A composition according to the invention comprising these three compounds is therefore particularly advantageous.
Un autre objet de l'invention consiste en une composition pharmaceutique comprenant un inhibiteur de la monoamine oxydase, un antagoniste présynaptique 5-HT^ et un agoniste 5-HT1A. Cette composition pharmaceutique comprend préférentiellement comme IMAO, la béfloxatone, comme antagoniste présynaptique 5-HT-y^, le pindolol, et comme agoniste 5-HT1A, la buspirone.Another subject of the invention consists of a pharmaceutical composition comprising a monoamine oxidase inhibitor, a 5-HT 3 presynaptic antagonist and a 5-HT 1A agonist. This pharmaceutical composition preferably comprises, as MAOIs, befloxatone, as 5-HT-y ^ presynaptic antagonist, pindolol, and as 5-HT1A agonist, buspirone.
Une composition selon la présente invention peut être présentée sous toutes formes appropriées à l'administration orale ou parentérale telles que comprimés, dragées, gélules, capsules, suspension ou solutions buvables ou injectables, le cas échéant, en association avec des excipients convenables. Dans le cadre de la présente invention, les formes orales sont préférées.A composition according to the present invention may be presented in any form suitable for oral or parenteral administration such as tablets, dragees, capsules, capsules, suspension or oral or injectable solutions, if necessary, in combination with suitable excipients. In the context of the present invention, oral forms are preferred.
Plus particulièrement, ces formes sont dosées pour permettre une administration journalière de :More particularly, these forms are dosed to allow daily administration of:
- 5 à 60 mg d'antagoniste présynaptique 5-HT1A,- 5 to 60 mg of 5-HT 1A presynaptic antagonist,
- 1 à 900 mg d' IMAO, - 5 à 80 mg d' agoniste 5-HT^.- 1 to 900 mg of MAOI, - 5 to 80 mg of 5-HT ^ agonist.
Les doses préférées sont de :The preferred doses are:
- 5 à 15 mg d'antagoniste présynaptique 5-HTlA,- 5 to 15 mg of 5-HT 1A presynaptic antagonist,
- 2,5 à 30 mg d' IMAO, - 20 à 60 mg d' agoniste 5-HT^.- 2.5 to 30 mg of MAOI, - 20 to 60 mg of 5-HT ^ agonist.
Une composition selon l'invention permet de réduire la posologie en l'un ou plusieurs des composés qui la constitue d'un facteur de 1 à 5 par rapport à la posologie conventionnelle de chacun de ces composés utilisé seul, et cela, tout en maintenant une efficacité thérapeutique. Un avantage majeur de l'invention réside dans le fait que les doses mises en oeuvre dans le cadre de l'invention se situent en dessous des doses classiques d'administration en monothérapie. On évite ainsi les effets secondaires liés à chacun des composés constitutifs de la composition selon l' invention.A composition according to the invention makes it possible to reduce the dosage to one or more of the compounds which constitute it by a factor of 1 to 5 compared to the conventional dosage of each of these compounds used alone, and this while maintaining therapeutic efficacy. A major advantage of the invention lies in the fact that the doses used in the context of the invention are below the conventional doses for administration as monotherapy. This avoids the side effects linked to each of the constituent compounds of the composition according to the invention.
La composition selon l'invention peut être administrée en une dose journalière unique ou en doses journalières fractionnées. Dans ce dernier cas, la composition selon l'invention peut être administrée en 2 à 4 prises.The composition according to the invention can be administered in a single daily dose or in divided daily doses. In the latter case, the composition according to the invention can be administered in 2 to 4 doses.
Pour l'association particulière béfloxatone + pindolol + buspirone, le facteur de réduction peut varier entre 2 et 5 par rapport à la posologie conventionnelle en chacun de ces composés utilisé seul, cela tout en maintenant une efficacité thérapeutique .For the particular combination of befloxatone + pindolol + buspirone, the reduction factor can vary between 2 and 5 compared to the conventional dosage in each of these compounds used alone, while maintaining therapeutic efficacy.
Une composition selon l'invention comprenant un IMAO, un antagoniste présynaptique 5-HTj^ et un agoniste 5-H j^ a fait l'objet d'études pharmacologiques qui ont mis en évidence un effet synergique inattendu sur le sommeil paradoxal et donc un intérêt certain comme antidépresseur. Les effets de cette composition ont été analysés sur l'étude du cycle veille-sommeil chez le rat implanté libre enregistré en période d' éclairement . Cette étude constitue un modèle permettant d'évaluer l'efficacité postsynaptique et la durée d'action des produits antidépresseurs. Selon Borbely A.A. et al., Brain Mechanisms of Sleep, D.J. McGinty et al. Raven press, New York, 1985, le processus de sommeil journalier du rat présente de fortes similitudes avec le processus de sommeil de l'homme, voire d'autres mammifères.A composition according to the invention comprising an MAOI, a presynaptic antagonist 5-HT j ^ and an agonist 5-H j ^ has been the subject of pharmacological studies which have demonstrated an unexpected synergistic effect on REM sleep and therefore a definite interest as an antidepressant. The effects of this composition were analyzed on the study of the sleep-wake cycle in the implanted free rat recorded during the lighting period. This study constitutes a model allowing to evaluate the postsynaptic efficacy and the duration of action of antidepressant products. According to Borbely AA et al., Brain Mechanisms of Sleep, DJ McGinty et al. Raven press, New York, 1985, the rat's daily sleep process has strong similarities to the sleep process of humans and even other mammals.
PROTOCOLE D'ÉTUDESTUDY PROTOCOL
Des électroencéphalogrammes (EEG) enregistrés au cours du sommeil sont utilisés pour tester les effets des différents composés administrés, comparatifs ou selon l'invention.Electroencephalograms (EEG) recorded during sleep are used to test the effects of the various compounds administered, comparative or according to the invention.
Le cycle veille-sommeil du rat libre est soumis à un rythme circadien régi par les conditions d' éclairement . Dans des conditions très strictes d'enregistrement (cycle lumière- obscurité de 12 heures / 12 heures, température 22 ± 1°C), le cycle veille-sommeil, sous la dépendance de l' "horloge biologique", suit un rythme très régulier, d'un jour à l'autre. Cette stabilité peut se retrouver pour des enregistrements partiels du nycthémère à condition de les effectuer à heures fixes (Depoortere H. et al., Neuropsychobiology, 16, 157-162, 1986) .The sleep-wake cycle of the free rat is subject to a circadian rhythm governed by the lighting conditions. Under very strict recording conditions (light / dark cycle of 12 hours / 12 hours, temperature 22 ± 1 ° C), the sleep-wake cycle, under the control of the "biological clock", follows a very regular rhythm , from one day to another. This stability can be found for partial recordings of the nycthemera provided that they are made at fixed times (Depoortere H. et al., Neuropsychobiology, 16, 157-162, 1986).
L' éclairement est maintenu de 7 h à 19 h et l'enregistrement, d'une durée de 6 h, s'effectue entre 11 h et 17 h.The lighting is maintained from 7 a.m. to 7 p.m. and the recording, which lasts 6 hours, takes place between 11 a.m. and 5 p.m.
Protocole chirurgicalSurgical protocol
Les rats mâles Sprague-Dawley de 200 à 220 g sont anesthésiés au méthohexital sodique (75 mg/kg en sous cutané) et mis en contention dans un cadre stéréotaxique. Les points d'incision et de pression sont infiltrés d'une solution à 2% de xylocaïne adrénalinée. Après résection des plans cutanés et musculaires, 6 électrodes constituées par de petites vis en acier inoxydable (0,9 mm de diamètre) sont mises en place au contact de la dure mère : 2 électrodes (1 par hémisphère) au niveau du cortex sensorimoteur (2 mm en arrière du bregma, 3 mm latéralement à la suture médiane) , 2 électrodes au niveau du cortex visuel (2 mm en avant du lambda et 2 mm latéralement) et 2 électrodes au niveau du cortex cérébelleux, électrode de référence (3 mm latéralement au plan médian) . Les électrodes sont reliées à un connecteur (Winchester, 7 contacts) par un fil d'argent. Les électrodes et le connecteur sont rendus solidaires à l'os par du ciment dentaire (Svedia Lamell resin cernent) .Male Sprague-Dawley rats weighing 200 to 220 g are anesthetized with sodium methohexital (75 mg / kg subcutaneously) and restrained in a stereotaxic setting. The incision and pressure points are infiltrated with a 2% solution of adrenaline xylocaine. After resection of the cutaneous and muscular planes, 6 electrodes constituted by small stainless steel screws (0.9 mm in diameter) are placed in contact with the dura mater: 2 electrodes (1 per hemisphere) at the level of the sensorimotor cortex ( 2 mm behind the bregma, 3 mm laterally to the median suture), 2 electrodes at the level of the visual cortex (2 mm in front of the lambda and 2 mm laterally) and 2 electrodes at the level of the cerebellar cortex, reference electrode (3 mm laterally to the median plane). The electrodes are connected to a connector (Winchester, 7 contacts) by a silver wire. The electrodes and the connector are made integral with the bone by dental cement (Svedia Lamell resin surround).
Enregistrement et stockage des donnéesData recording and storage
Les rats sont reliés au système d'enregistrement (Grass modèle 79D) par un câble souple muni d'un connecteur tournant (APCL 12 voies, air précision) . Le signal est amplifié et filtré (1 à 16 Hz, 48 dB/octave) . L'ensemble des signaux EEG est enregistré sur un enregistreur magnétique (Data recorder RTP-802 A, Kyowa) . Les signaux EEG sont numérisés (fréquence d'échantillonnage à 70 Hz) sur ordinateur (PC Compaq Deskpro 486/33, programme Axotape, Axon instrument) . Le signal EEG digitalisé est calculé selon les paramètres de Hjorth "activité/complexité" par période de 4 secondes sur les 6 heures d'enregistrement.The rats are connected to the recording system (Grass model 79D) by a flexible cable fitted with a rotating connector (APCL 12-way, air precision). The signal is amplified and filtered (1 to 16 Hz, 48 dB / octave). All the EEG signals are recorded on a magnetic recorder (Data recorder RTP-802 A, Kyowa). EEG signals are digitized (sampling frequency at 70 Hz) on a computer (PC Compaq Deskpro 486/33, Axotape program, Axon instrument). The digitized EEG signal is calculated according to the Hjorth "activity / complexity" parameters per 4-second period over the 6 hours of recording.
L' analyse du signal EEG des voies sensorimotrices et visuelles par les paramètres de Hjorth permet de caractériser les différents stades du cycle veille-sommeil : éveil, sommeil classique (somnolence + sommeil lent) et le sommeil paradoxal (SP) (Depoortere H. et Granger P., Methods of Sleep Research, Kubicki St., Hermann W.M. (Eds.), Stuttgart, Fischer, 37-45, 1985) . Un contrôle visuel des tracés est également effectué.Analysis of the EEG signal from the sensorimotor and visual pathways using Hjorth parameters makes it possible to characterize the different stages of the sleep-wake cycle: wakefulness, classic sleep (drowsiness + slow sleep) and sleep paradoxical (SP) (Depoortere H. and Granger P., Methods of Sleep Research, Kubicki St., Hermann WM (Eds.), Stuttgart, Fischer, 37-45, 1985). A visual check of the tracks is also carried out.
EnregistrementRecording
Après 3 semaines de récupération post-opératoire, les rats sont placés dans des cylindres de plexiglas (60 cm de diamètre) avec nourriture et boisson ad libitum. Avant chaque expérience les rats sont habitués à l'enceinte pendant au minimum 3 jours. Chaque enregistrement dure 6 heures (de 11 h à 17 h) et chaque session expérimentale se compose de 3 jours : 1 jour contrôle (véhicule : sérum physilogique + 1 goutte de Tween 80), 1 jour "produit" et 1 jour contrôle 24 h après l'administration du "produit".After 3 weeks of post-operative recovery, the rats are placed in plexiglass cylinders (60 cm in diameter) with food and drink ad libitum. Before each experiment, the rats are accustomed to the enclosure for at least 3 days. Each recording lasts 6 hours (from 11 a.m. to 5 p.m.) and each experimental session consists of 3 days: 1 control day (vehicle: physiological serum + 1 drop of Tween 80), 1 "product" day and 1 24-hour control day after the administration of the "product".
Les "produits" à étudier ou le véhicule sont administrées par voie intrapéritonéale (i.p.) 15 minutes avant l' enregistrement . La durée totale et l'analyse horaire de chaque stade sont évaluées ainsi que la latence d'apparition du SP. L'analyse statistique des résultats est réalisée à partir du test "t" de Student pour séries appariées (Depoortere H. et al., Neuropsychobi ology, 32, 214-221, 1995 ; Depoortere H. et al., Pharmacol . Biochem. Behav. , 51(4), 571-576, 1995).The "products" to be studied or the vehicle are administered intraperitoneally (i.p.) 15 minutes before recording. The total duration and hourly analysis of each stage are evaluated as well as the latency of onset of SP. Statistical analysis of the results is carried out using Student's "t" test for paired series (Depoortere H. et al., Neuropsychobi ology, 32, 214-221, 1995; Depoortere H. et al., Pharmacol. Biochem. Behav., 51 (4), 571-576, 1995).
L'expérimentation sur les "produits" a été menée en trois volets :The experimentation on "products" was carried out in three parts:
- en monothérapie (comparatif) :- as monotherapy (comparative):
doses uniques de béfloxatone (3 mg/kg i.p.), de pindolol (1 mg/kg i.p.) ou de buspirone (0,3 mg/kg i.p.),single doses of befloxatone (3 mg / kg i.p.), pindolol (1 mg / kg i.p.) or buspirone (0.3 mg / kg i.p.),
- en bithérapie (comparatif) :- in dual therapy (comparative):
association de 3 mg/kg i.p. de béfloxatone et de 1 mg/kg i.p. de pindolol ou association de 3 mg/kg i.p. de béfloxatone et de 0,3 mg/kg i.p. de buspirone. - en trithérapie (selon l'invention) :combination of 3 mg / kg ip of befloxatone and 1 mg / kg ip of pindolol or combination of 3 mg / kg ip of befloxatone and 0.3 mg / kg ip of buspirone. - in triple therapy (according to the invention):
association de 3 mg/kg i.p. de béfloxatone avec 1 mg/kg i.p. de pindolol et 0,3 mg/kg i.p. de buspirone.combination of 3 mg / kg i.p. of befloxatone with 1 mg / kg i.p. pindolol and 0.3 mg / kg i.p. of buspirone.
RESULTATSRESULTS
Les résultats obtenus sont rassemblés dans le tableau. Ils sont exprimés en variation par rapport aux valeurs contrôles. Pour le calcul de ces variations, chaque rat est son propre témoin.The results obtained are collated in the table. They are expressed as a variation from the control values. For the calculation of these variations, each rat is its own witness.
L'annexe présente sous forme d'histogrammes, les résultats relatifs au sommeil paradoxal, moyennes sur l'ensemble des rats étudiés, heure par heure durant les 6 premières heures de la session expérimentale décrite précédemment. Cette représentation permet tout particulièrement de visualiser la durée d' action, définie ci- après.The appendix presents, in the form of histograms, the results relating to REM sleep, averaged over all of the rats studied, hour by hour during the first 6 hours of the experimental session described above. This representation makes it possible in particular to view the duration of action, defined below.
On entend ici par "durée d'action" la durée, exprimée en heure, pendant laquelle on observe une diminution statistiquement significative (p « 0,05 ou p « 0,01, distingués respectivement par * et ** dans le tableau et l'annexe) ou une disparition du sommeil paradoxal comparativement aux enregistrements contrôles (administration du véhicule seul) .The term “duration of action” is understood here to mean the duration, expressed in hours, during which a statistically significant decrease is observed (p “0.05 or p“ 0.01, distinguished respectively by * and ** in the table and l 'appendix) or a disappearance of REM sleep compared to the control records (vehicle administration only).
Les résultats rassemblés dans le tableau et l'annexes sont commentés ci-après.The results collated in the table and the appendices are commented below.
On observe :We observe :
- en monothérapie,- in monotherapy,
- pour la béfloxatone, une augmentation de la durée de l'éveil (+24%) aux dépens notamment du SP (-28%) dont la latence d'apparition de la première phase est augmentée de 58 minutes. La durée d'action de la béfloxatone s'observe pendant les deux premières heures. - pour le pindolol, une réduction de la durée totale du SP (-20%). La durée d'action se limite à la première heure après 1' injection,- for befloxatone, an increase in the duration of wakefulness (+ 24%) at the expense in particular of SP (-28%) whose latency of onset of the first phase is increased by 58 minutes. The duration of action of befloxatone is observed during the first two hours. - for pindolol, a reduction in the total duration of SP (-20%). The duration of action is limited to the first hour after the injection,
- pour la buspirone, aucun effet sur la durée totale du SP et une augmentation de la latence d'apparition de la première phase de 28 minutes. Sa durée d'action est limitée à la première heure,- for buspirone, no effect on the total duration of SP and an increase in the latency of onset of the first phase by 28 minutes. Its duration of action is limited to the first hour,
- en bithérapie.- in dual therapy.
- pour l'association béfloxatone + pindolol, une augmentation de la durée totale de l'éveil (+44%), une diminution de la durée totale du SP (-59%) et une durée d'action d'environ deux heures, - pour l'association béfloxatone + buspirone, les effets sont comparables à l'association précédente puisque la diminution de la durée totale du SP est de -56%, et la durée d'action est d'environ deux heures,- for the combination of befloxatone + pindolol, an increase in the total duration of wakefulness (+ 44%), a decrease in the total duration of SP (-59%) and a duration of action of approximately two hours, - for the combination of befloxatone + buspirone, the effects are comparable to the previous association since the reduction in the total duration of SP is -56%, and the duration of action is approximately two hours,
- en trithérapie,- in triple therapy,
une potentialisation des effets antidépresseurs qui dépasse de façon très surprenante les valeurs que l'on pouvait attendre au regard des résultats de bithérapie et monothérapie. La durée totale de l'éveil augmente de 72% au dépens notamment du SP. La durée d'action atteint 5 heures. La durée totale du SP diminue significative ent de plus de 80% et la latence d'apparition de la première phase de SP est retardée de 245 minutes. Les effets de la béfloxatone sont donc à la fois potentialisés en intensité et en durée (augmentation de la durée d'action : 5 heures au lieu de 2 heures en monothérapie). De plus, aucun phénomène de rebond, c'est à dire de récupération ou de compensation de la dette en SP, provoquée par l'administration de la composition, n'apparaît 24 heures après l'injection des produits. Ceci est caractéristique d'une bonne tolérance de l'association.a potentiation of the antidepressant effects which very surprisingly exceeds the values that one could expect with regard to the results of dual therapy and monotherapy. The total duration of arousal increases by 72% at the expense of SP, in particular. The duration of action reaches 5 hours. The total duration of MS decreases significantly by more than 80% and the latency of onset of the first phase of MS is delayed by 245 minutes. The effects of befloxatone are therefore both potentiated in intensity and duration (increase in the duration of action: 5 hours instead of 2 hours as monotherapy). In addition, no rebound phenomenon, that is to say recovery or compensation of the debt in MS, caused by the administration of the composition, appears 24 hours after the injection of the products. This is characteristic of a good tolerance of the association.
Ces résultats montrent la puissance d'une composition selon l'invention en tant que nouveau traitement des différentes formes de dépression, par exemple la dépression majeure, dysthimies, psychoses maniacodépressives, etc. On obtient une composition très efficace sur les états de veille-sommeil, et notamment au niveau du SP, une augmentation du délai d'apparition et une réduction de la durée totale de SP. Ces effets vont dans le sens d'un réajustement du sommeil chez les déprimés.These results show the power of a composition according to the invention as a new treatment for various forms of depression, for example major depression, dysthimia, manic-depressive psychosis, etc. A very effective composition is obtained on the sleep-wake states, and in particular at the level of MS, an increase in the time of appearance and a reduction in the total duration of MS. These effects point towards a readjustment of sleep in the depressed.
Le phénomène de synergie permet d'administrer des doses plus faibles d' IMAO et évite ainsi les effets secondaires, notamment l'effet tyramine, tout en maintenant une efficacité thérapeutique .The synergy phenomenon makes it possible to administer lower doses of MAOIs and thus avoids the side effects, in particular the tyramine effect, while maintaining a therapeutic efficacy.
Ce traitement permet, de plus, une amélioration globale de la qualité du sommeil. En effet, l'augmentation de la durée totale de l'éveil, provoquée par l'administration de la composition selon l'invention peut également accentuer le "processus S", (Borbely A.A., Expérimental Brain Research, Suppl . 8, Springer-Verlag Berlin, Heidelberg, 1984) réduit chez les dépressifs. De fait, les rythmes lents et la durée du sommeil profond ne sont pas altérés après la phase initiale d'éveil, tandis que le SP continue d'être réduit.This treatment also allows an overall improvement in the quality of sleep. Indeed, the increase in the total duration of wakefulness, provoked by the administration of the composition according to the invention can also accentuate the "process S", (Borbely AA, Experimental Brain Research, Suppl. 8, Springer- Verlag Berlin, Heidelberg, 1984) reduced in depressed people. In fact, the slow rhythms and duration of deep sleep are not altered after the initial phase of arousal, while the SP continues to be reduced.
En outre, le renforcement de la transmission serotoninergique postsynaptique, responsable notamment de la réduction du sommeil paradoxal, et le blocage des autorécepteurs sérotoninergiques devraient permettre de réduire le délai d'apparition de l'effet thérapeutique. L'absence de phénomène de rebond 24 heures après le traitement, laisse entrevoir une bonne tolérance et l'absence de tachyphylaxie lors d'un traitement prolongé.In addition, the strengthening of postsynaptic serotonergic transmission, responsible in particular for the reduction of REM sleep, and the blocking of serotoninergic autoreceptors should make it possible to reduce the time of onset of the therapeutic effect. The absence of rebound phenomenon 24 hours after treatment suggests a good tolerance and the absence of tachyphylaxis during prolonged treatment.
D'autres avantages de la composition selon l'invention peuvent être notés :Other advantages of the composition according to the invention can be noted:
- la composition confère une activité anxiolytique notamment due à la présence d'un agoniste 5-HT^ de type buspirone,the composition confers an anxiolytic activity in particular due to the presence of a 5-HT 3 agonist of the buspirone type,
- la composition permet d'influencer la chronobiologie notamment par le biais des propriétés antagonistes β-bloquant de type pindolol. La composition pharmaceutique selon l'invention peut également être mise en oeuvre en vue du traitement de l'anxiété généralisée, des phobies sociales, des attaques de panique, des désordres cognitifs, des psychoses, des troubles du sommeil et des troubles obsessifs compulsifs. the composition makes it possible to influence the chronobiology in particular by means of the β-blocking antagonistic properties of the pindolol type. The pharmaceutical composition according to the invention can also be used for the treatment of generalized anxiety, social phobias, panic attacks, cognitive disorders, psychoses, sleep disorders and obsessive-compulsive disorders.
INFLUENCE SUR LES ETATS DE VEILLE-SOMMEIL CHEZ LE RAT IMPLANTE LIBRE EN PERIODE D'ECLAIREMENTINFLUENCE ON SLEEP-SLEEP STATES IN FREE IMPLANT RAT IN ILLUMINATION PERIOD
Figure imgf000019_0001
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000019_0002
* p « 0,005, ** p « 0,01 : signification par rapport au contrôle* p "0.005, ** p" 0.01: significance in relation to the control
N : nombre de rats testés,N: number of rats tested,
SP % : variation de la durée totale du SP en % par rapport au contrôle Lat SP min : variation du temps de latence en min par rapport au contrôle Ev. % : variation de la durée de l'éveil en % par rapport au contrôle SP%: variation of the total duration of the SP in% compared to the Lat control SP min: variation of the latency time in min compared to the Ev control. %: variation of the duration of wakefulness in% compared to the control

Claims

Revendications claims
1. Une composition pharmaceutique comprenant un inhibiteur de la monoamine oxydase, un antagoniste présynaptique 5-HT1A et un agoniste 5-HT1A comme produit de combinaison pour une utilisation simultanée, séparée ou étalée dans le temps pour le traitement des différentes formes de dépression.1. A pharmaceutical composition comprising a monoamine oxidase inhibitor, a 5-HT 1A presynaptic antagonist and a 5-HT 1A agonist as a combination product for simultaneous, separate or time use for the treatment of different forms of depression .
2. Une composition pharmaceutique comprenant un inhibiteur de la monoamine oxydase, un antagoniste présynaptique 5-HT1A et un agoniste 5-HT-^ comme produit de combinaison pour une utilisation simultanée, séparée ou étalée dans le temps pour le traitement de l'anxiété généralisée, des phobies sociales, des attaques de panique, des désordres cognitifs, des psychoses, des troubles du sommeil et des troubles obsessifs compulsifs .2. A pharmaceutical composition comprising a monoamine oxidase inhibitor, a presynaptic 5-HT 1A antagonist and a 5-HT- ^ agonist as a combination product for simultaneous, separate or time use for the treatment of anxiety generalized, social phobias, panic attacks, cognitive disorders, psychoses, sleep disturbances and obsessive compulsive disorders.
3. Une composition pharmaceutique selon l'une des revendications 1 et 2 caractérisée en ce qu'elle est destinée à l'administration par voie orale.3. A pharmaceutical composition according to one of claims 1 and 2 characterized in that it is intended for oral administration.
4. Une composition pharmaceutique selon l'une des revendications 1 à 3, caractérisée en ce que l'inhibiteur de la monoamine oxydase est choisi dans le groupe constitué par :4. A pharmaceutical composition according to one of claims 1 to 3, characterized in that the monoamine oxidase inhibitor is chosen from the group consisting of:
- les IMAO de type A tels que la béfloxatone, le moclobémide, la brofaromine, la phénoxathine, l'esuprone, le befol, le RS 8359 (Sankyo), le T794 (Tanabé) , le KP 9MAOI type A such as befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, RS 8359 (Sankyo), T794 (Tanabé), KP 9
(Krenitsky, USA), le E 2011 (Eisei) , la toloxatone, le pirlindole, l' amiflamine, la sercloremine, la bazinaprine, la clorgyline, le tetrindole,(Krenitsky, USA), E 2011 (Eisei), toloxatone, pirlindole, amiflamine, sercloremine, bazinaprine, clorgyline, tetrindole,
- les IMAO de type B tels que le lazabemide, le milacémide, la caroxazone, l'IFO, le L-deprényl, la mofégiline, la rasagéline, la pargyline, - les IMAO de type mixte tels que la phénelzine, le nialamide, le tranylcypromine, l' iproniazid, l' isocarboxide.- MAOIs of type B such as lazabemide, milacemide, caroxazone, IFO, L-deprenyl, mofegiline, rasagelin, pargyline, - MAOIs of mixed type such as phenelzine, nialamide, tranylcypromine, iproniazid, isocarboxide.
5. Une composition pharmaceutique selon la revendication 4, caractérisée en ce que l'inhibiteur de la monoamine oxydase est la béfloxatone.5. A pharmaceutical composition according to claim 4, characterized in that the monoamine oxidase inhibitor is befloxatone.
6. Une composition pharmaceutique selon l'une des revendications 1 à 5, caractérisée en ce que l'antagoniste présynaptique6. A pharmaceutical composition according to one of claims 1 to 5, characterized in that the presynaptic antagonist
5-HT^ est le pindolol.5-HT ^ is pindolol.
7. Une composition pharmaceutique selon l'une des revendications 1 à 5, caractérisée en ce que l' agoniste 5- HT^ est choisi parmi : le E 4414 (Esteve) , la gepirone, l' ipsapirone, le LY 293284 (Lilly), le AP 521 (Asahi), le AZ 16596 (Asahi), le BMS 184111 (Bristol Myers Squibb), le DDR 203901 (Roche), le DDR 205852 (Yamanouchi), le DDR 208978 (Asahi Chemical), le DDR 211278 (Bayer), le DDR 212219 (Lundbeck), le F 12439 (P Fabre), le FCE 23892 (Farmitalia) , le L 0068 / F 11440 (P Fabre), le LY 274600 / LY 274601 (Lilly), le LY 301317 (Lilly), le LY 297996 (Lilly), le NAD 299 (Astra) , le composé référencé sous le n° 3828 dans la base de données Pharamprojects (Lilly), le composé référencé sous le n° 4040 dans la base de données Pharmaprojects7. A pharmaceutical composition according to one of claims 1 to 5, characterized in that the agonist 5- HT ^ is chosen from: E 4414 (Esteve), gepirone, ipsapirone, LY 293284 (Lilly) , AP 521 (Asahi), AZ 16596 (Asahi), BMS 184111 (Bristol Myers Squibb), DDR 203901 (Roche), DDR 205852 (Yamanouchi), DDR 208978 (Asahi Chemical), DDR 211278 ( Bayer), DDR 212219 (Lundbeck), F 12439 (P Fabre), FCE 23892 (Farmitalia), L 0068 / F 11440 (P Fabre), LY 274600 / LY 274601 (Lilly), LY 301317 ( Lilly), LY 297996 (Lilly), NAD 299 (Astra), the compound referenced under No. 3828 in the Pharamprojects database (Lilly), the compound referenced under No. 4040 in the Pharmaprojects database
(Lundbeck) , le composé référencé sous le n° 4827 dans la base de données Pharmaprojects (Medinnova) , le S 14671 (Servier), le S 215521 (Servier), le U 92016A (Upjohn), le WAY 100802 (AHP / Wyeth Ayerst), le WY 48723 (Wyeth Ayerst), l'ebalzotan / NAE 086 (Astra), le S 15535 (Servier), l'EMD 67478 (E Merck), , l'alnespirone / S 20499 (Servier), le BAYx 3702 (Bayer), le lesopitron (Esteve Boots), la zalospirone, le flesinoxan, la tandospirone, le CP 110330 / CP 119333 (Pfizer), le EMD 77697 (E Merck), le LY 315535 (Lilly / Roberts) , le OPC 14523 (Otsuka) , le composé référencé sous le n° 4375 dans la base de données Pharmaprojects (Solvay) , le BIMT 17 / flibanserin (Boehringer Ingelheim) , la binospirone, l'EM 56551 (E Merck), l' adatanserine / WY 50324 (AHP / Weyth-Ayerst) , le BMS 181101 (Bristol Myers Squibb), l'EMD 68843 (E Merck), le piricapiron, le SR 57746 (Sanofi), la bromerguride, le FG 5865 (Kabi Pharmacia), le GR 103691 (Glaxo Wellcome), le HT 90 B (Chugai) ou, de préférence, la buspirone. (Lundbeck), the compound referenced under No. 4827 in the Pharmaprojects database (Medinnova), S 14671 (Servier), S 215521 (Servier), U 92016A (Upjohn), WAY 100802 (AHP / Wyeth Ayerst), WY 48723 (Wyeth Ayerst), ebalzotan / NAE 086 (Astra), S 15535 (Servier), EMD 67478 (E Merck),, alnespirone / S 20499 (Servier), BAYx 3702 (Bayer), lesopitron (Esteve Boots), zalospirone, flesinoxan, tandospirone, CP 110330 / CP 119333 (Pfizer), EMD 77697 (E Merck), LY 315535 (Lilly / Roberts), OPC 14523 (Otsuka), the compound referenced under No. 4375 in the Pharmaprojects database (Solvay), BIMT 17 / flibanserin (Boehringer Ingelheim), binospirone, EM 56551 (E Merck), adatanserine / WY 50324 (AHP / Weyth-Ayerst), BMS 181101 (Bristol Myers Squibb), EMD 68843 (E Merck), piricapiron, SR 57746 (Sanofi), bromerguride, FG 5865 (Kabi Pharmacia), GR 103691 (Glaxo Wellcome), HT 90 B (Chugai) or, preferably buspirone.
8. Une composition pharmaceutique selon l'une des revendications 1 à 3, caractérisée en ce que l'inhibiteur de la monoamine oxydase est la béfloxatone, l'antagoniste présynaptique 5-HT^ est le pindolol et l' agoniste 5-HT1A est la buspirone.8. A pharmaceutical composition according to one of claims 1 to 3, characterized in that the monoamine oxidase inhibitor is befloxatone, the presynaptic antagonist 5-HT ^ is pindolol and the agonist 5-HT 1A is buspirone.
9. Une composition pharmaceutique selon l'une des revendications 1 à 8 caractérisée en ce qu'elle comprend entre 1 et 900 mg d'inhibiteur de la monoamine oxydase, entre 5 et 60 mg d'antagoniste présynaptique 5-HT^ et entre 5 et 80 mg d' agoniste 5-HT^.9. A pharmaceutical composition according to one of claims 1 to 8 characterized in that it comprises between 1 and 900 mg of monoamine oxidase inhibitor, between 5 and 60 mg of presynaptic antagonist 5-HT ^ and between 5 and 80 mg of 5-HT ^ agonist.
10. Une composition pharmaceutique selon l'une des revendications 1 à 8 caractérisée en ce qu'elle comprend entre 2,5 et 30 mg d'inhibiteur de la monoamine oxydase, entre 5 et 15 mg d'antagoniste présynaptique 5-HT^ et entre 20 et 60 mg d' agoniste 5-HT1A.10. A pharmaceutical composition according to one of claims 1 to 8 characterized in that it comprises between 2.5 and 30 mg of monoamine oxidase inhibitor, between 5 and 15 mg of presynaptic antagonist 5-HT ^ and between 20 and 60 mg of 5-HT1A agonist.
11. Une composition pharmaceutique comprenant un inhibiteur de la monoamine oxydase, un antagoniste présynaptique 5-HT^ et un agoniste 5-HT^.11. A pharmaceutical composition comprising a monoamine oxidase inhibitor, a presynaptic 5-HT ^ antagonist and a 5-HT ^ agonist.
12. Une composition pharmaceutique selon la revendication 11, caractérisée en ce que, l'IMAO est la béfloxatone, l'antagoniste présynaptique 5-HT^ est le pindolol et l' agoniste 5-HT1A est la buspirone.12. A pharmaceutical composition according to claim 11, characterized in that the MAOI is befloxatone, the presynaptic antagonist 5-HT ^ is pindolol and the agonist 5-HT1A is buspirone.
13. Médicament caractérisé en ce qu'il est constitué d'un inhibiteur de la monoamine oxydase, d'un antagoniste présynaptique 5-HT^ et d'un agoniste 5-HT1A.13. Drug characterized in that it consists of a monoamine oxidase inhibitor, a presynaptic 5-HT ^ antagonist and a 5-HT 1A agonist.
14. Utilisation d'un inhibiteur de la monoamine oxydase, d'un antagoniste présynaptique 5-HT1A et d'un agoniste 5-HT^ pour la fabrication d'un médicament destiné au traitement des différentes formes de dépression, comme dépression majeure, dysthimies, psychoses maniacodépressives, etc.14. Use of a monoamine oxidase inhibitor, a 5-HT 1A presynaptic antagonist and a 5-HT 2 agonist for the manufacture of a medicament intended for the treatment of various forms of depression, such as major depression, dysthimias, manic-depressive psychoses, etc.
15. Utilisation d'un inhibiteur de la monoamine oxydase, d'un antagoniste présynaptique 5-HT1A et d'un agoniste 5-HT^ pour la fabrication d'un médicament destiné au traitement de l'anxiété généralisée, des phobies sociales, des attaques de panique, des désordres cognitifs, des psychoses, des troubles du sommeil et des toubles obsessifs compulsifs.15. Use of a monoamine oxidase inhibitor, a presynaptic 5-HT 1A antagonist and a 5-HT ^ agonist for the manufacture of a medicament for the treatment of generalized anxiety, social phobias, panic attacks, cognitive disorders, psychoses, sleep disorders and obsessive compulsive disorder.
16. Procédé d'obtention d'un médicament antidépresseur caractérisé en ce que l'on met en oeuvre simultanément, de manière séparée ou étalée dans le temps un inhibiteur de la monoamine oxydase, un antagoniste présynaptique 5-HT1A et un agoniste 5-HT1A. 16. Method for obtaining an antidepressant medication, characterized in that a monoamine oxidase inhibitor, a presynaptic 5-HT 1A antagonist and a 5- agonist are used simultaneously, separately or spread over time HT 1A .
PCT/FR1998/001929 1997-09-17 1998-09-10 Pharmaceutical compositions containing a monoamine oxydase inhibitor and their use in therapy WO1999013879A1 (en)

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US6110961A (en) * 1996-09-11 2000-08-29 Krenitsky Pharmaceuticals, Inc. Phenoxathin derivatives as inhibitors of monoamine oxidase
FR2792529A1 (en) * 1999-04-26 2000-10-27 Sod Conseils Rech Applic Patches containing 1,2,3,4-tetrahydro-8-(5-isoxazolyl)-N,N-diisopropyl-2-naphthalenamine for transdermal treatment of irritable bowel syndrome

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US20040024036A1 (en) * 2000-08-01 2004-02-05 Anne Charlier Pharmaceutical composition for transdermal delivery of befloxatone
DK1256343T3 (en) 2001-05-11 2006-10-30 Juergen K Dr Beck Flibanserin for the treatment of extrapyramidal movement disorders

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SCHWEITZER I. ET AL: "A review of the use of augmentation therapy for the treatment of resistant depression: Implications for the clinician", AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY, 1997, 31/3 (340-352), AUSTRALIA, XP002066942 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6110961A (en) * 1996-09-11 2000-08-29 Krenitsky Pharmaceuticals, Inc. Phenoxathin derivatives as inhibitors of monoamine oxidase
FR2792529A1 (en) * 1999-04-26 2000-10-27 Sod Conseils Rech Applic Patches containing 1,2,3,4-tetrahydro-8-(5-isoxazolyl)-N,N-diisopropyl-2-naphthalenamine for transdermal treatment of irritable bowel syndrome
WO2000064444A1 (en) * 1999-04-26 2000-11-02 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Novel pharmaceutical compositions comprising 2-isoxazole-8-aminotetralin derivatives
US6685959B1 (en) 1999-04-26 2004-02-03 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Pharmaceutical compositions comprising 2-isoxazoles-8-aminotetralin derivatives

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