[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2000006160A1 - Treating depression with a combination of fluoxetine (prozac), pindolol (visken) and buspirone (buspar) - Google Patents

Treating depression with a combination of fluoxetine (prozac), pindolol (visken) and buspirone (buspar) Download PDF

Info

Publication number
WO2000006160A1
WO2000006160A1 PCT/FR1999/001825 FR9901825W WO0006160A1 WO 2000006160 A1 WO2000006160 A1 WO 2000006160A1 FR 9901825 W FR9901825 W FR 9901825W WO 0006160 A1 WO0006160 A1 WO 0006160A1
Authority
WO
WIPO (PCT)
Prior art keywords
agonist
antagonist
serotonin reuptake
presynaptic
pharmaceutical composition
Prior art date
Application number
PCT/FR1999/001825
Other languages
French (fr)
Inventor
Henri Depoortere
Original Assignee
Sanofi-Synthelabo
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi-Synthelabo filed Critical Sanofi-Synthelabo
Priority to AU49167/99A priority Critical patent/AU4916799A/en
Publication of WO2000006160A1 publication Critical patent/WO2000006160A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to pharmaceutical compositions comprising an inhibitor of serotonin reuptake, a presynaptic 5-HT 1A antagonist and a 5-HT 1A agonist, as well as their therapeutic application.
  • One of the current techniques for treating depression is based on increasing central serotonergic neurotransmission by increasing the concentration of serotonin in the synaptic cleft. This increase in serotonin concentration can be obtained, in particular, by monoamine oxidase inhibitors and serotonin reuptake inhibitors (1RS).
  • the serotonin reuptake inhibitor causes serotonin to accumulate in the synaptic cleft, but also in the region of cell bodies, where somatodendritic autoreceptors of the 5-HT 1A type are located, which control the neuronal activity of serotonergic cells and largely the release of serotonin.
  • Somatodendritic autoreceptors when activated by a high concentration of serotonin, decrease the frequency of serotonin discharge from serotonergic neurons of the dorsal raphe.
  • a disadvantage of treatment with antidepressants in general lies in the late onset of the therapeutic effect (average delay ⁇ 3 weeks).
  • the doses of serotonin reuptake inhibitor necessary to observe a therapeutic effect are such that they can promote the appearance of nausea, headache, sexual dysfunction and in particular impaired ejaculation, restlessness, nervousness related to acathesis, anorexia, insomnia etc.
  • the Applicant has observed that the combination of a serotonin reuptake inhibitor and pindolol does not make it possible, for a given serotonin reuptake inhibitor, to increase the time of latency of appearance of the first phase of REM sleep, nor to decrease the total duration of REM sleep, by sufficient. It also does not allow to significantly reduce the dose of the inhibitor, or even the presynaptic 5-HT 1A antagonist, so as to * reduce the risk of occurrence of side effects, while preserving therapeutic efficacy.
  • a first subject of the invention consists of a pharmaceutical composition comprising at least one serotonin reuptake inhibitor, the therapeutic efficacy of which is considerably increased compared to known compositions comprising this same 1RS.
  • a second subject of the invention consists of a pharmaceutical composition comprising at least one 1RS in an effective dose reduced compared to known compositions comprising this same 1RS.
  • a third subject of the invention consists of a pharmaceutical composition comprising at least one 1RS 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 1RS.
  • the subject of the present invention is therefore a pharmaceutical composition
  • a pharmaceutical composition comprising a serotonin reuptake inhibitor, a presynaptic 5-HT 1A antagonist and a 5-HT 1A agonist as a combination product for simultaneous, separate or time-dispersed use for the treatment of depression.
  • spontaneous 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 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, - the administration, at the same time, of the three compounds of the composition according to the invention included in separate pharmaceutical forms.
  • use spread over time means: - 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 its own pharmaceutical form or, - the successive administration of the compounds of the composition according to the invention, each included in a separate 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 1RS.
  • the therapeutic effect of a given 1RS 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 occurrence of side effects.
  • this composition according to the invention makes it possible to achieve the expected therapeutic effect more quickly, by eliminating the delay in onset of desensitization by the presynaptic 5-HT 1A inhibitor and by reinforcing serotonergic transmission by the agonist.
  • the 1RS can be a selective or mixed serotonin 1RS.
  • 1RS we can cite: the following selective SRs: sertraline, paroxetine, fluvoxamine, fluoxetine, citalopram, cericlamine, * dapoxetine, the following mixed SRs: venlafaxine, nefazodone, milnacipran, MCI 225 (Mitsubishi Kasei), l 'EMD 68843 (Merck KgaA), clemoprol, BMS 181101 (Bristol Myers Squibb), YM 35992 (Yamanouchi), NS 2389 (NeuroSearch), EMD 80084 (Merck KgaA), EF 7412 (CEPA / Ecros).
  • 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 1A agonist, or a partial 5-HT 1A agonist, with respect to * postsynaptic affinity, such as for example buspirone.
  • a selective antagonist of the somatodendritic 5-HT 1A autoreceptors 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.
  • Fluoxetine is most particularly preferred as an IRS.
  • 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 an inhibitor of serotonin reuptake, a presynaptic 5-HT 1A antagonist and a 5-HT 1A agonist.
  • This pharmaceutical composition preferably comprises as 1RS, fluoxetine, as a presynaptic antagonist 5-HT 1A , pindolol, and as an agonist 5-HT1A, 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 usual 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 a 1RS, a 5-HT 1A presynaptic antagonist and a 5-HT 1A agonist has been the subject of pharmacological studies which have demonstrated an unexpected synergistic effect on REM sleep and therefore an advantage. certain as an antidepressant.
  • the effects of this composition were analyzed on the study of the sleep-wake cycle in the free implanted 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 screws made of stainless steel (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 on 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 experience the rats are used to the enclosure for at least 3 days. Each recording lasts 6 hours (from 1 hrs to 5 hrs) and each experimental session consists of 3 days: 1 control day (vehicle: physiological serum + 1 drop of Tween 80), 1 "product" day and 1 control day 24 h 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.
  • the statistical analysis of the results is carried out using Student's "t" test for paired series (Depoortere H. et al., Neuropsychobiology, 32, 214-221, 1995; Depoortere H. et al., Pharmacol. Biochem. Behav ., 51 (4), 571-576, 1995).
  • 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 appendices 1 to 3) or a reduction of at least 50% of REM sleep compared to the control recordings (administration of the vehicle alone).
  • - for fluoxetine (1 and 3 mg / kg ip), a reduction in the duration of SP respectively by 14 and 21%, whose latency of onset of the first phase is increased by 6 and 66 minutes respectively.
  • the duration of action of fluoxetine is observed during the first two hours.
  • the dose of lmg / kg is not very active, - for pindolol (0.1 and 1 mg / kg ip), a reduction in the total duration of the SP by 13 and 20% respectively.
  • the duration of action is limited to the first hour after the injection of lmg / kg ip.
  • the dose of 0.1 mg / kg ip is not very active.
  • - 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,
  • compositions according to the invention show the power of a composition according to the invention as a new treatment for the various forms of depression, for example major depression, dysthimias, manic-depressive psychoses, 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 onset and a reduction in the total duration of MS. These effects point towards a readjustment of sleep in the depressed.
  • the synergy phenomenon makes it possible to administer lower doses of 1RS and thus avoids the side effects, in particular on the cardiovascular level, while maintaining a therapeutic effectiveness.
  • 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", (Borbély 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 serotonergic autoreceptors should allow reduce the time to onset of the therapeutic effect.
  • the absence of a rebound phenomenon after 24 hours of the _ "treatment would expect a good tolerance and lack of tachyphylaxis during prolonged treatment.
  • the composition confers an anxiolytic activity in particular due to the presence of a 5-HT 1A agonist of the buspirone type, the composition makes it possible to influence the chronobiology in particular through the ⁇ -blocking antagonist 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention concerns pharmaceutical compositions containing a serotonin uptake inhibitor, a 5-HT1A presynaptic antagonist and a 5-HT1A agonist as combination product for simultaneous, separate or prolonged use for treating various forms of depression.

Description

TRAITEMENT DE LA DEPRESSION AVEC UNE COMBINAISON DE FLUOXETINE (PROZAC), PINDOLOL (VISKEN) ET BUSPIRONE (BUSPAR)TREATMENT OF DEPRESSION WITH A COMBINATION OF FLUOXETINE (PROZAC), PINDOLOL (VISKEN) AND BUSPIRONE (BUSPAR)
La présente invention a pour objet des compositions pharmaceutiques comprenant un inhibiteur de la recapture de la serotonine, un antagoniste présynaptique 5-HT1A et un agoniste 5-HT1A, ainsi que leur application en thérapeutique.The present invention relates to pharmaceutical compositions comprising an inhibitor of serotonin reuptake, a presynaptic 5-HT 1A antagonist and a 5-HT 1A agonist, as well as their therapeutic application.
L'une des techniques actuelles de traitement de la dépression repose sur l'augmentation de la neurotransmission sérotoninergique centrale par le biais d'une augmentation de la concentration de la serotonine dans la fente synaptique. Cette augmentation de la concentration en serotonine peut être obtenue, notamment, par les inhibiteurs de la monoamine oxydase et les inhibiteurs de la recapture de la serotonine (1RS) .One of the current techniques for treating depression is based on increasing central serotonergic neurotransmission by increasing the concentration of serotonin in the synaptic cleft. This increase in serotonin concentration can be obtained, in particular, by monoamine oxidase inhibitors and serotonin reuptake inhibitors (1RS).
Plus spécifiquement, l'inhibiteur de la recapture de la serotonine entraîne l'accumulation de la serotonine dans la fente synaptique, mais aussi dans la région des corps cellulaires, où sont localisés les autorécepteurs somatodendritiques du type 5-HT1A, qui contrôlent l'activité neuronale des cellules sérotoninergiques et en grande partie la libération de serotonine. Les autorécepteurs somatodendritiques, lorsqu'ils sont activés par une concentration élevée de serotonine, diminuent la fréquence de décharge en serotonine des neurones sérotoninergiques du raphé dorsal. Puis, cet effet de diminution de fréquence de décharge s'estompe car les autorécepteurs somatodendritiques du type 5-HT1A se désensibilisent, permettant ainsi un rétablissement de la libération de serotonine 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 . Psychia try, 51, 14-20, 1990) .More specifically, the serotonin reuptake inhibitor causes serotonin to accumulate in the synaptic cleft, but also in the region of cell bodies, where somatodendritic autoreceptors of the 5-HT 1A type are located, which control the neuronal activity of serotonergic cells and largely the release of serotonin. Somatodendritic autoreceptors, when activated by a high concentration of serotonin, decrease the frequency of serotonin discharge from serotonergic neurons of the dorsal raphe. Then, this effect of decreasing the frequency of discharge fades because the somatodendritic autoreceptors of the 5-HT 1A 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. Psychia try, 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 serotonine, et de la dopamine ; les inhibiteurs de la monoamine oxydase) , réside dans l'apparition tardive de l'effet thérapeutique (délai moyen^de 3 semaines). En outre, les doses d'inhibiteur de la recapture de la serotonine nécessaires pour observer un effet thérapeutique sont telles qu'elles peuvent favoriser l'apparition de nausées, mal de tête, dysfonctionnement sexuel et en particulier l'altération de l' éjaculation, agitation, nervosité apparentée à l'acathésie, anorexie, insomnie etc. D'autre part, il existe des effets secondaires communs aux différents types d'antidépresseurs parmi lesquels on peut citer l'hypomanie, le délire, l'abaissement du niveau de vigilance (sédation, somnolence), hypotension orthostatique et interactions médicamenteuses. Ces effets secondaires généraux et spécifiques aux 1RS sont décrits dans J. Baldessarini, "pharmacological basis of therapeutics" . 9th Edition (1996), Goodman & Gilman's, Chapter 19, 431-455 et Michel Schoderet, "des concepts fondamentaux aux applications thérapeutiques", Pharmacologie, Edition Slatkine (1988) .A disadvantage of treatment with antidepressants in general (for example: norepinephrine, serotonin, and dopamine reuptake inhibitors; monoamine oxidase inhibitors), lies in the late onset of the therapeutic effect (average delay ^ 3 weeks). In addition, the doses of serotonin reuptake inhibitor necessary to observe a therapeutic effect are such that they can promote the appearance of nausea, headache, sexual dysfunction and in particular impaired ejaculation, restlessness, nervousness related to acathesis, anorexia, insomnia etc. On the other hand, there are side effects common to the different types of antidepressants among which one can quote hypomania, delirium, the lowering of the level of vigilance (sedation, drowsiness), orthostatic hypotension and drug interactions. These general and specific side effects of 1RS are described in J. Baldessarini, "pharmacological basis of therapeutics". 9 th Edition (1996), Goodman &Gilman's, Chapter 19, 431-455 and Michel Schoderet, "from fundamental concepts to therapeutic applications", Pharmacology, Slatkine Edition (1988).
Le lien entre la neurotransmission sérotoninergique et la régulation du sommeil paradoxal a été décrite dans Adrien J. , le sommeil normal et pa thologique, 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 sérotoninergique 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 .The link between serotonergic neurotransmission and the regulation of REM sleep has been described in Adrien J., 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 sleep REM sleep: increased latency onset of the first phase of REM sleep and reduction of the total * REM sleep time. 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-HT1A en association avec soit un inhibiteur sélectif de la recapture de la serotonine soit un inhibiteur de la monoamine oxydase 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 . Psychia try, 51, 248-251, 1994 ; Blier P. et al., J. Clin . Psychopharmacol . , 15, 217-222, 1995).Treatment with a 5-HT 1A antagonist in combination with either a selective serotonin reuptake inhibitor or a monoamine oxidase inhibitor has been reported to increase the effectiveness of antidepressant therapy in the depressed and shorten the time to appearance of the antidepressant effect (Artigas F. et al., Arch. Gen. Psychia try, 51, 248-251, 1994; Blier P. et al., J. Clin. Psychopharmacol., 15, 217-222, 1995).
Un certain nombre d'études en double aveugle tendent à prouver une meilleure réponse antidépressante des inhibiteurs de la recapture de la serotonine tels que la fluoxétine et la paroxétine lorsqu'ils sont associés à du pindolol (Perez et al., Lancet, 349, 1594-7, 1997 ; Thomas P. et al., Effective disorders and antidepressants, P.1.121, S173, 1997 ; Zanardi R. et al., Journal of Clinical Psychopharmacology, 17(6), 446- 450, 1997 ; Tome M.B. et al., Interna tional Clinical Psychopharmacology, 12, 81-89, 1997). A l'inverse d'autres études ont révélé que l'administration de pindolol en sus d'un inhibiteur de la recapture de la serotonine tel que la fluoxétine ne conduisait pas à une augmentation de l'efficacité du traitement antidépresseur (Charney et al., Am . J. Psychia try, 154, 37-43, 1997, Berman R.M. et al., Am . J. Psychia try, 154:1, 37-43, 1997 ; Moreno F.A. et al., J Clin Psychia try, 58:10, 437439, 1997).A number of double-blind studies tend to demonstrate a better antidepressant response of serotonin reuptake inhibitors such as fluoxetine and paroxetine when combined with pindolol (Perez et al., Lancet, 349, 1594 -7, 1997; Thomas P. et al., Effective disorders and antidepressants, P.1.121, S173, 1997; Zanardi R. et al., Journal of Clinical Psychopharmacology, 17 (6), 446- 450, 1997; Tome MB et al., International Clinical Psychopharmacology, 12, 81-89, 1997). Conversely, other studies have revealed that the administration of pindolol in addition to a serotonin reuptake inhibitor such as fluoxetine does not lead to an increase in the effectiveness of antidepressant treatment (Charney et al. , Am. J. Psychia try, 154, 37-43, 1997, Berman RM et al., Am. J. Psychia try, 154: 1, 37-43, 1997; Moreno FA et al., J Clin Psychia try, 58:10, 437439, 1997).
En tout état de cause, la demanderesse a pu constater, que l'association d'un inhibiteur de la recapture de la serotonine et de pindolol ne permet pas, pour un inhibiteur sélectif de la recapture de serotonine 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 de l'inhibiteur, voire en antagoniste présynaptique 5-HT1A, de sorte à * diminuer les risques d'apparition des effets secondaires, tout en préservant une efficacité thérapeutique.In any event, the Applicant has observed that the combination of a serotonin reuptake inhibitor and pindolol does not make it possible, for a given serotonin reuptake inhibitor, to increase the time of latency of appearance of the first phase of REM sleep, nor to decrease the total duration of REM sleep, by sufficient. It also does not allow to significantly reduce the dose of the inhibitor, or even the presynaptic 5-HT 1A antagonist, so as to * reduce the risk of occurrence of side effects, while preserving therapeutic efficacy.
Un premier objet de l'invention consiste en une composition pharmaceutique comprenant au moins un inhibiteur de la recapture de la serotonine, dont l'efficacité thérapeutique est considérablement accrue par rapport aux compositions connues comprenant ce même 1RS.A first subject of the invention consists of a pharmaceutical composition comprising at least one serotonin reuptake inhibitor, the therapeutic efficacy of which is considerably increased compared to known compositions comprising this same 1RS.
Un deuxième objet de l'invention consiste en une composition pharmaceutique comprenant au moins un 1RS en une dose efficace réduite par rapport aux compositions connues comprenant ce même 1RS . Un troisième objet de l'invention consiste en une composition pharmaceutique comprenant au moins un 1RS 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 1RS.A second subject of the invention consists of a pharmaceutical composition comprising at least one 1RS in an effective dose reduced compared to known compositions comprising this same 1RS. A third subject of the invention consists of a pharmaceutical composition comprising at least one 1RS 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 1RS.
La présente invention a alors pour objet une composition pharmaceutique comprenant un inhibiteur de la recapture de la serotonine, 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 de la dépression.The subject of the present invention is therefore a pharmaceutical composition comprising a serotonin reuptake inhibitor, a presynaptic 5-HT 1A antagonist and a 5-HT 1A agonist as a combination product for simultaneous, separate or time-dispersed use for the treatment of depression.
On entend par "utilisation simultanée" l'administration des composés de la composition selon l'invention compris dans une seule et même forme pharmaceutique. 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, - l'administration, en même temps, des trois composés de la composition selon l' invention compris dans des formes pharmaceutiques distinctes. *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 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, - 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" : - 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, - l'administration successive des composés de la composition selon l'invention, compris chacun dans une forme pharmaceutique distincte.The term "use spread over time" means: - 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 its own pharmaceutical form or, - 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 1RS donné. En d'autres termes, l'effet thérapeutique d'un 1RS 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. 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 sérotoninergique par l' agoniste b~HT^ .In general, the composition according to the invention considerably increases the effectiveness of the treatment of depression, for a given 1RS. In other words, the therapeutic effect of a given 1RS 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 occurrence of side effects. In addition, this composition according to the invention makes it possible to achieve the expected therapeutic effect more quickly, by eliminating the delay in onset of desensitization by the presynaptic 5-HT 1A inhibitor and by reinforcing serotonergic transmission by the agonist. b ~ HT ^.
Dans le cadre de l'invention, l' 1RS peut être un 1RS sélectif de la serotonine ou mixte. A titre d' 1RS on peut citer : les 1RS sélectifs suivants : la sertraline, la paroxétine, la fluvoxamine, la fluoxétine, le citalopram, la cericlamine,* la dapoxétine, les 1RS mixtes suivants : la venlafaxine, le nefazodone, le milnacipran, le MCI 225 (Mitsubishi Kasei) , l'EMD 68843 (Merck KgaA) , le clemoprol, le BMS 181101 (Bristol Myers Squibb), le YM 35992 (Yamanouchi) , le NS 2389 (NeuroSearch) , l'EMD 80084 (Merck KgaA), l'EF 7412 (CEPA/Ecros) .In the context of the invention, the 1RS can be a selective or mixed serotonin 1RS. As 1RS we can cite: the following selective SRs: sertraline, paroxetine, fluvoxamine, fluoxetine, citalopram, cericlamine, * dapoxetine, the following mixed SRs: venlafaxine, nefazodone, milnacipran, MCI 225 (Mitsubishi Kasei), l 'EMD 68843 (Merck KgaA), clemoprol, BMS 181101 (Bristol Myers Squibb), YM 35992 (Yamanouchi), NS 2389 (NeuroSearch), EMD 80084 (Merck KgaA), EF 7412 (CEPA / Ecros).
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 AY 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 /(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), AY 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), 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 . L' agoniste 5-HT1A peut être soit un agoniste 5-HT1A complet, soit un agoniste 5-HT1A partiel, vis-à-vis de * l'affinité postsynaptique, comme par exemple la buspirone.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. The 5-HT 1A agonist can be either a complete 5-HT 1A agonist, or a partial 5-HT 1A 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-HT1A somatodendritiques, qui contrôle l'activité neuronale et la libération de serotonine 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 antagonist of the somatodendritic 5-HT 1A autoreceptors 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.
La fluoxétine est tout particulièrement préférée à titre d'IRS. Le pindolol et la buspirone sont particulièrement préférés, respectivement en tant qu'antagoniste présynaptique 5-HT1A et agoniste 5-HT1A.Fluoxetine is most particularly preferred as an IRS. 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 recapture de la serotonine, un antagoniste présynaptique 5-HT1A et un agoniste 5-HT1A. Cette composition pharmaceutique comprend préférentiellement comme 1RS, la fluoxétine, comme antagoniste présynaptique 5-HT1A, le pindolol, et comme agoniste 5-HT1A, la buspirone.Another subject of the invention consists of a pharmaceutical composition comprising an inhibitor of serotonin reuptake, a presynaptic 5-HT 1A antagonist and a 5-HT 1A agonist. This pharmaceutical composition preferably comprises as 1RS, fluoxetine, as a presynaptic antagonist 5-HT 1A , pindolol, and as an agonist 5-HT1A, 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 g d' antagoniste présynaptique 5-HT1A, - 1 à 150 mg d' 1RS ,- 5 to 60 g of 5-HT 1A presynaptic antagonist, - 1 to 150 mg of 1RS,
- 5 à 80 mg d' agoniste 5-HT1A. * - 5 to 80 mg of 5-HT 1A agonist. *
Les doses préférées sont de :The preferred doses are:
- 5 à 15 mg d'antagoniste présynaptique 5-HT1A,- 5 to 15 mg of 5-HT 1A presynaptic antagonist,
- 5 à 30 mg d' 1RS, - 20 à 60 mg d' agoniste 5-HTlA.- 5 to 30 mg of 1RS, - 20 to 60 mg of 5-HT lA 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 usuelles 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 usual 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 fluoxétine + 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 fluoxetine + 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 1RS, un antagoniste présynaptique 5-HT1A et un agoniste 5-HT1A 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 a 1RS, a 5-HT 1A presynaptic antagonist and a 5-HT 1A agonist has been the subject of pharmacological studies which have demonstrated an unexpected synergistic effect on REM sleep and therefore an advantage. certain as an antidepressant. The effects of this composition were analyzed on the study of the sleep-wake cycle in the free implanted 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 anesthesiés 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 xylocalne 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 xylocalne. After resection of the cutaneous and muscular planes, 6 electrodes constituted by small screws made of stainless steel (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 on 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 REM sleep (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 1J. 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 experience the rats are used to the enclosure for at least 3 days. Each recording lasts 6 hours (from 1 hrs to 5 hrs) and each experimental session consists of 3 days: 1 control day (vehicle: physiological serum + 1 drop of Tween 80), 1 "product" day and 1 control day 24 h 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., Neuropsychobiology, 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. The statistical analysis of the results is carried out using Student's "t" test for paired series (Depoortere H. et al., Neuropsychobiology, 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 fluoxétine (1 et 3 mg/kg i.p.), de pindolol (0,1 et 1 mg/kg i.p.) ou de buspirone (0,3 mg/kg i.p.),single doses of fluoxetine (1 and 3 mg / kg i.p.), pindolol (0.1 and 1 mg / kg i.p.) or buspirone (0.3 mg / kg i.p.),
- en bithérapie (comparatif) :- in dual therapy (comparative):
association de 1 mg/kg i.p. de fluoxétine et de 1 mg/kg i.p. de pindolol,combination of 1 mg / kg i.p. fluoxetine and 1 mg / kg i.p. pindolol,
- en trithérapie (selon l'invention) :- in triple therapy (according to the invention):
- association de 1 mg/kg i.p. de fluoxétine avec 0,1 mg/kg i.p. de pindolol et 0,3 mg/kg i.p. de buspirone,- combination of 1 mg / kg i.p. fluoxetine with 0.1 mg / kg i.p. pindolol and 0.3 mg / kg i.p. buspirone,
- association de 1 mg/kg i.p. de fluoxétine avec 1 mg/kg i.p. de pindolol et 0,3 mg/kg i.p. de buspirone,- combination of 1 mg / kg i.p. fluoxetine with 1 mg / kg i.p. pindolol and 0.3 mg / kg i.p. buspirone,
- association de 3 mg/kg i.p. de fluoxétine avec 1 mg/kg i.p. de pindolol et 0,3 mg/kg i.p. de buspirone,- combination of 3 mg / kg i.p. fluoxetine with 1 mg / kg i.p. pindolol and 0.3 mg / kg i.p. buspirone,
RESULTATS Les résultats obtenus sont rassemblés dans le tableau en annexe 1. Ils sont exprimés en variation par rapport aux « valeurs contrôles. Pour le calcul de ces variations, chaque rat est son propre témoin. N est le nombre de rats testés, SP % est la variation de la durée totale du SP en % par rapport au contrôle, Lat SP min est la variation du temps de latence en min par rapport au contrôle et Ev. % est la variation de la durée de l'éveil en % par rapport au contrôle. Les figures en annexe 2 et 3 présentent 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. La durée de SP en ordonnée est exprimée en secondes.RESULTS The results obtained are collated in the table in appendix 1. They are expressed as a variation with respect to the "control values. For the calculation of these variations, each rat is its own witness. N is the number of rats tested, SP% is the variation of the total duration of the SP in% compared to the control, Lat SP min is the variation of the latency time in min compared to the control and Ev. % is the variation of the duration of wakefulness in% compared to the control. The figures in appendix 2 and 3 present, 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. The duration of SP on the ordinate is expressed in seconds.
Cette représentation permet tout particulièrement de visualiser la durée d'action, définie ci-après.This representation makes it possible in particular to visualize 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 les annexes 1 à 3) ou une diminution d'au moins 50% 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 appendices 1 to 3) or a reduction of at least 50% of REM sleep compared to the control recordings (administration of the vehicle alone).
Les résultats rassemblés dans les annexes 1 à 3 sont commentés ci-après.The results gathered in appendices 1 to 3 are commented below.
On observe :We observe :
- en monothérapie,- in monotherapy,
- pour la fluoxétine (1 et 3 mg/kg i.p.), une diminution de la durée du SP respectivement de 14 et 21%, dont la latence d' apparition de la première phase est augmentée respectivement de 6 et 66 minutes. La durée d'action de la fluoxétine s'observe pendant les deux premières heures. La dose de lmg/kg s'avère peu active, - pour le pindolol (0,1 et 1 mg/kg i.p.), une réduction de la durée totale du SP respectivement de 13 et 20%. La durée » d'action se limite à la première heure après l'injection de lmg/kg i.p. La dose de 0,1 mg/kg i.p. s'avère peu active. - 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 fluoxetine (1 and 3 mg / kg ip), a reduction in the duration of SP respectively by 14 and 21%, whose latency of onset of the first phase is increased by 6 and 66 minutes respectively. The duration of action of fluoxetine is observed during the first two hours. The dose of lmg / kg is not very active, - for pindolol (0.1 and 1 mg / kg ip), a reduction in the total duration of the SP by 13 and 20% respectively. The duration of action is limited to the first hour after the injection of lmg / kg ip. The dose of 0.1 mg / kg ip is not very active. - 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,
une augmentation des effets antidépresseurs de la fluoxétine est observée mais les effets restent limités et portent surtout sur la latence d'apparition du SP. - association de fluoxétine (1 mg/kg i.p.) + pindolol (1 mg/kg i.p.). La durée totale du SP diminue significativement de 20% et la latence d'apparition est retardée de 48 minutes. La durée d'action est limitée à 2 heures,an increase in the antidepressant effects of fluoxetine is observed but the effects remain limited and relate mainly to the latency of onset of SP. - combination of fluoxetine (1 mg / kg i.p.) + pindolol (1 mg / kg i.p.). The total duration of MS significantly decreases by 20% and the onset latency is delayed by 48 minutes. The duration of action is limited to 2 hours,
en trithérapie,in triple therapy,
une potentialisation des effets antidépresseurs de la fluoxétine qui dépasse de façon très surprenante les valeurs que l'on pouvait attendre au regard des résultats de monothérapie, et ce pour une dose donnée en fluoxétine.a potentiation of the antidepressant effects of fluoxetine which very surprisingly exceeds the values that one could expect with regard to the results of monotherapy, and this for a given dose of fluoxetine.
- association de fluoxétine (1 mg/kg i.p.) + buspirone (0,3 mg/kg i.p.) + pindolol (0,1 mg/kg i.p.) : La durée totale de SP diminue significativement de 30% et la latence d'apparition est retardée de 66 minutes. La durée d'action est de 2 heures,- combination of fluoxetine (1 mg / kg ip) + buspirone (0.3 mg / kg ip) + pindolol (0.1 mg / kg ip): The total duration of MS decreases significantly by 30% and the latency onset is delayed by 66 minutes. The duration of action is 2 hours,
- association de fluoxétine (1 mg/kg i.p.) + buspirone (0,3 mg/kg i.p.) + pindolol (1 mg/kg i.p.) : La durée totale de SP diminue significativement de 44 % et la latence d'apparition de la première phase de SP est retardée de 122 minutes. La durée d'action est de 3 heures,- combination of fluoxetine (1 mg / kg ip) + buspirone (0.3 mg / kg ip) + pindolol (1 mg / kg ip): The total duration of MS decreases significantly by 44% and the latency of onset of first phase of MS is delayed by 122 minutes. The duration of action is 3 hours,
- association de fluoxétine (3 mg/kg i.p.) + buspirone (0,3 mg/kg i.p.) + pindolol (1 mg/kg i.p.) : La durée totale de l'éveil augmente de 45% au dépens notamment du SP. La durée totale du SP diminue significativement de 66% et la latence d'apparition de la première phase de SP est retardée de 20Q minutes. La durée d'action atteint 5 heures.- combination of fluoxetine (3 mg / kg ip) + buspirone (0.3 mg / kg ip) + pindolol (1 mg / kg ip): The total duration of arousal increases by 45% at the expense of SP in particular. The duration total of SP decreases significantly by 66% and the latency of onset of the first phase of SP is delayed by 20Q minutes. The duration of action reaches 5 hours.
Les effets de la fluoxétine sont donc à la fois potentialises en intensité et en durée (augmentation de la durée d'action : jusqu'à 5 heures au lieu de 2 heures en monothérapie et en bithérapie) . 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.The effects of fluoxetine are therefore both potentiated in intensity and duration (increase in the duration of action: up to 5 hours instead of 2 hours in monotherapy and bitherapy). 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. Le phénomène de synergie permet d'administrer des doses plus faibles d' 1RS et évite ainsi les effets secondaires, notamment sur le plan cardiovasculaire, tout en maintenant une efficacité thérapeutique.These results show the power of a composition according to the invention as a new treatment for the various forms of depression, for example major depression, dysthimias, manic-depressive psychoses, 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 onset and a reduction in the total duration of MS. These effects point towards a readjustment of sleep in the depressed. The synergy phenomenon makes it possible to administer lower doses of 1RS and thus avoids the side effects, in particular on the cardiovascular level, while maintaining a therapeutic effectiveness.
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", (Borbély 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", (Borbély 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 sérotoninergique 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, permettrait de s'attendre à 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 serotonergic autoreceptors should allow reduce the time to onset of the therapeutic effect. The absence of a rebound phenomenon after 24 hours of the _ "treatment would expect a good tolerance and lack 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-HT1A de type buspirone, - la composition permet d'influencer la chronobiologie notamment par le biais des propriétés antagonistes β-bloquant de type pindolol.the composition confers an anxiolytic activity in particular due to the presence of a 5-HT 1A agonist of the buspirone type, the composition makes it possible to influence the chronobiology in particular through the β-blocking antagonist properties of the pindolol type.
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 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 EINFLUENCE ON SLEEP-SLEEP STATES IN THE FREE IMPLANT RAT E
Figure imgf000018_0001
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000018_0002
annexe 2annex 2
Influence de 1 mg/kg ip de Fluoxétine (N=6)Influence of 1 mg / kg ip of Fluoxetine (N = 6)
Figure imgf000019_0001
Figure imgf000019_0001
Influence de 0,3 mg/kg ip de Buspirone (N=6)Influence of 0.3 mg / kg ip of Buspirone (N = 6)
Figure imgf000019_0002
Figure imgf000019_0002
Influence de 0,1 et 1 mg/kg ip de Pindolol (N=6)Influence of 0.1 and 1 mg / kg ip of Pindolol (N = 6)
Figure imgf000019_0003
Figure imgf000019_0003
Influence de 1 mg kg îp de Fluoxétine + 0,1 mg/kg ip de Pindolol + 0,3 mg/kg ip de Buspirone (N=5)Influence of 1 mg kg îp of Fluoxetine + 0.1 mg / kg ip of Pindolol + 0.3 mg / kg ip of Buspirone (N = 5)
Figure imgf000019_0004
Figure imgf000019_0004
Influence de 1 mg/kg ip de Fluoxétine + 1 mg/kg ip de Pindolol + 0,3 mg/kg ip de Buspirone (N=4)Influence of 1 mg / kg ip of Fluoxetine + 1 mg / kg ip of Pindolol + 0.3 mg / kg ip of Buspirone (N = 4)
Figure imgf000019_0005
Figure imgf000019_0005
Véhicule HH Produit 24 h *p<0,05 **p<0,01 annexe 3Vehicle HH Product 24 h * p <0.05 ** p <0.01 annex 3
Influence de 3 mg/kg ip de Fluoxétine (N=5)Influence of 3 mg / kg ip of Fluoxetine (N = 5)
Figure imgf000020_0001
Figure imgf000020_0001
Influence de 0,3 mg/kg ip de Buspirone (N=6)Influence of 0.3 mg / kg ip of Buspirone (N = 6)
Figure imgf000020_0002
Figure imgf000020_0002
Influence de 0,1 et 1 mg/kg ip de Pindolol (N=6)Influence of 0.1 and 1 mg / kg ip of Pindolol (N = 6)
Figure imgf000020_0003
Figure imgf000020_0003
Influence de 3 mg/kg ip de Fluoxétine + 1 mg kg ip de Pindolol + 0,3 mg kg ip de Buspirone (N=6)Influence of 3 mg / kg ip of Fluoxetine + 1 mg kg ip of Pindolol + 0.3 mg kg ip of Buspirone (N = 6)
Figure imgf000020_0004
Figure imgf000020_0004
I — | Véhicule H Produit 24 h * p<0.05 ' FX0.01 I - | Vehicle H Product 24 h * p <0.05 'FX0.01

Claims

Revendications claims
1. Une composition pharmaceutique comprenant un inhibiteur de la recapture de la serotonine, 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 serotonin reuptake inhibitor, a 5-HT 1A presynaptic antagonist and a 5-HT 1A agonist as a combination product for simultaneous, separate or use over time for the treatment of different forms of depression.
2. Une composition pharmaceutique comprenant un inhibiteur de la recapture de la serotonine, un antagoniste présynaptique2. A pharmaceutical composition comprising a serotonin reuptake inhibitor, a presynaptic antagonist
5-HT1A et un agoniste 5-HT1A 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.5-HT 1A and a 5-HT 1A agonist as a combination product for simultaneous, separate or time-dispersed use for the treatment of generalized anxiety, social phobias, panic attacks, cognitive disorders, psychoses , sleep disorders and obsessive compulsive disorder.
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 recapture de la serotonine est choisi dans le groupe constitué par :4. A pharmaceutical composition according to one of claims 1 to 3, characterized in that the serotonin reuptake inhibitor is chosen from the group consisting of:
Parmi les 1RS sélectifs : la sertraline, la paroxétine, la fluvoxamine, la fluoxétine, le citalopram, la cericlamine, la dapoxétine, parmi les 1RS mixtes : la venlafaxine, le nefazodone, le milnacipran, le MCI 225 (Mitsubishi Kasei) , l'EMD 68843 (Merck KgaA), le clemoprol, le BMS 181101 (Bristol Myers Squibb), le YM 35992 (Yamanouchi), le NS 2389 (NeuroSearch) , l'EMD 80084 (Merck KgaA), l'EF 7412 (CEPA/Ecros) .Among the selective SRs: sertraline, paroxetine, fluvoxamine, fluoxetine, citalopram, cericlamine, dapoxetine, among the mixed SRs: venlafaxine, nefazodone, milnacipran, MCI 225 (Mitsubishi Kasei), EMD 68843 (Merck KgaA), clemoprol, BMS 181101 (Bristol Myers Squibb), YM 35992 (Yamanouchi), NS 2389 (NeuroSearch), EMD 80084 (Merck KgaA), EF 7412 (CEPA / Ecros) ).
5. Une composition pharmaceutique selon la revendication 4, caractérisée en ce que l'inhibiteur de la recapture de la serotonine est la fluoxétine.5. A pharmaceutical composition according to claim 4, characterized in that the serotonin reuptake inhibitor is fluoxetine.
6. Une composition pharmaceutique selon l'une des revendications 1 à 5, caractérisée en ce que l'antagoniste présynaptique 5-HT1A est le pindolol. * 6. A pharmaceutical composition according to one of Claims 1 to 5, characterized in that the presynaptic antagonist 5-HT 1A is pindolol. *
7. Une composition pharmaceutique selon l'une des revendications 1 à 5, caractérisée en ce que l' agoniste 5- HT1A 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 2122197. A pharmaceutical composition according to one of claims 1 to 5, characterized in that the agonist 5- HT 1A 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), 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 /(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) , 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 .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 recapture de la sérotonin est la fluoxétine, l'antagoniste présynaptique 5-HT1A 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 serotonin reuptake inhibitor is fluoxetine, the presynaptic antagonist 5-HT 1A 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 150 mg d'inhibiteur de recapture de la serotonine, entre 5 et 60 mg d'antagoniste présynaptique 5-HT1A et entre 5 et 80 mg d' agoniste 5-HT1A.9. A pharmaceutical composition according to one of claims 1 to 8 characterized in that it comprises between 1 and 150 mg of serotonin reuptake inhibitor, between 5 and 60 mg of presynaptic antagonist 5-HT 1A and between 5 and 80 mg of 5-HT 1A agonist.
10. Une composition pharmaceutique selon l'une des revendications 1 à 8 caractérisée en ce qu'elle comprend entre 5 et 30 mg d'inhibiteur de la recapture de la serotonine, entre 5 et 15 mg d'antagoniste présynaptique 5- HT1A 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 5 and 30 mg of serotonin reuptake inhibitor, between 5 and 15 mg of presynaptic antagonist 5- HT 1A and between 20 and 60 mg of 5-HT1A agonist.
11. Une composition pharmaceutique comprenant un inhibiteur de la recapture de la serotonine, un antagoniste présynaptique 5-HT1A et un agoniste 5-HT1A.11. A pharmaceutical composition comprising an inhibitor of serotonin reuptake, a presynaptic 5-HT 1A antagonist and a 5-HT 1A agonist.
12. Une composition pharmaceutique selon la revendication 11, caractérisée en ce que, l'inhibiteur de la recapture de la serotonine est la fluoxétine, l'antagoniste présynaptique 5- HT1A est le pindolol et l' agoniste 5-HT1A est la buspirone.12. A pharmaceutical composition according to claim 11, characterized in that, the serotonin reuptake inhibitor is fluoxetine, the presynaptic 5-HT 1A antagonist is pindolol and the 5-HT1A agonist is buspirone.
13. Médicament caractérisé en ce qu'il est constitué d'un inhibiteur de la recapture de la serotonine, d'un antagoniste présynaptique 5-HT1A et d'un agoniste 5-HT1A.13. Medicinal product, characterized in that it consists of a serotonin reuptake inhibitor, a presynaptic 5-HT 1A antagonist and a 5-HT 1A agonist.
14. Utilisation d'un inhibiteur de la recapture de la serotonine, d'un antagoniste présynaptique 5-HT1A et d'un agoniste 5-HT1A 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 serotonin reuptake inhibitor, a 5-HT 1A presynaptic antagonist and a 5-HT 1A agonist for the manufacture of a medicament for the treatment of various forms of depression, such as depression major, dysthimies, manic-depressive psychoses, etc.
15. Utilisation d'un inhibiteur de la recapture de la serotonine, d'un antagoniste présynaptique 5-HT1A et d'un agoniste 5-HT1A 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 troubles obsessifs compulsifs. «15. Use of a serotonin reuptake inhibitor, a 5-HT 1A presynaptic antagonist and a 5-HT 1A agonist for the manufacture of a medicament for the treatment of generalized anxiety, phobias social, panic attacks, cognitive disorders, psychosis, sleep disturbance 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 recapture de la serotonine, un antagoniste présynaptique 5- HT1A et un agoniste 5-HT1A. 16. Method for obtaining an antidepressant drug, characterized in that a serotonin reuptake inhibitor, a presynaptic 5-HT 1A antagonist and an agonist are used simultaneously, separately or spread over time 5-HT 1A .
PCT/FR1999/001825 1998-07-28 1999-07-26 Treating depression with a combination of fluoxetine (prozac), pindolol (visken) and buspirone (buspar) WO2000006160A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU49167/99A AU4916799A (en) 1998-07-28 1999-07-26 Treating depression with a combination of fluoxetine (prozac), pindolol (visken)and buspirone (buspar)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR98/09603 1998-07-28
FR9809603A FR2781671A1 (en) 1998-07-28 1998-07-28 PHARMACEUTICAL COMPOSITIONS CONTAINING SEROTONIN RECAPTURE INHIBITOR AND THERAPEUTIC USE THEREOF

Publications (1)

Publication Number Publication Date
WO2000006160A1 true WO2000006160A1 (en) 2000-02-10

Family

ID=9529079

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FR1999/001825 WO2000006160A1 (en) 1998-07-28 1999-07-26 Treating depression with a combination of fluoxetine (prozac), pindolol (visken) and buspirone (buspar)

Country Status (3)

Country Link
AU (1) AU4916799A (en)
FR (1) FR2781671A1 (en)
WO (1) WO2000006160A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000072832A2 (en) * 1999-05-27 2000-12-07 Merck Patent Gmbh Novel use of 1-[4-(cyanoindol-3yl)butyl]-4-(carbamoyl-benzofuran-5yl)-piperazine and its physiologically acceptable salts
JP2004522692A (en) * 2000-03-10 2004-07-29 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング Novel use of (R)-(-)-2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl] -chroman and its physiologically acceptable salts
US7094786B2 (en) 2003-01-13 2006-08-22 Dynogen Pharmaceuticals, Inc. Method of treating nausea, vomiting, retching or any combination thereof
US7115606B2 (en) 2003-04-04 2006-10-03 Dynogen Pharmaceuticals, Inc. Method of treating lower urinary tract disorders
JP2008526700A (en) * 2004-12-30 2008-07-24 シュバルツ ファルマ アクチェンゲゼルシャフト Oxygen-containing phenyldiazepan carboxamides and cyclized phenyl piperazine carboxamides and use as dopamine D3 antagonists
US7718705B1 (en) 1999-09-03 2010-05-18 Eli Lilly And Company Methods of using rapid-onset selective serotonin reuptake inhibitors for treating sexual dysfunction
CN113880815A (en) * 2020-07-03 2022-01-04 中国药科大学 Indole derivatives and preparation method and application thereof
US11977085B1 (en) 2023-09-05 2024-05-07 Elan Ehrlich Date rape drug detection device and method of using same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0687472A2 (en) * 1994-06-16 1995-12-20 Eli Lilly And Company Potentiation of drug response by a serotonin 1A receptor antagonist
EP0792649A1 (en) * 1996-02-29 1997-09-03 Eli Lilly And Company Treatment of sleep disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0687472A2 (en) * 1994-06-16 1995-12-20 Eli Lilly And Company Potentiation of drug response by a serotonin 1A receptor antagonist
EP0792649A1 (en) * 1996-02-29 1997-09-03 Eli Lilly And Company Treatment of sleep disorders

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
CADIEUX R. J.: "Practical management of treatment-resistant depression", AMERICAN FAMILY PHYSICIAN, December 1998 (1998-12-01), pages 1 - 6, XP002102288 *
DEVANE C.L. ET AL: "1998 Guide to psychotropic drug interactions", MBL COMMUNICATIONS, HTTP://MBLCOMMUNICATIONS.COM/PP998_DEVANE.HTLM, XP002102289 *
DEVANE CL ET AL, PRIMARY PSYCHIATRY, vol. 5, no. 9, 1998 *
MAJERONI B. A. ET AL: "The pharmacologic treatment of depression", JOURNAL OF THE AMERICAN BOARD OF FAMILY PRACTICE, vol. 11, no. 2, March 1998 (1998-03-01), http://www.medscape.com/ABFP/JABFP/1998/v11.n02/fp1102.05.maje/fp1102.05.maje.html, pages 127 - 139, XP002102290 *
NEMEROFF C B: "AUGMENTATION STRATEGIES IN PATIENTS WITH REFRACTORY DEPRESSION", DEPRESSION AND ANXIETY, 1 January 1996 (1996-01-01), pages 169 - 181, XP002066941 *
PEREZ M ET AL: "Design and synthesis of new potent, silent 5-HT1A antagonists by covalent coupling of aminopropanol derivatives with selective serotonin reuptake inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 8, no. 23, 1 December 1998 (1998-12-01), pages 3423-3428, XP004143770 *
PUZANTIAN, TALIA (1) ET AL: "Does the addition of pindolol accelerate or enhance the response to selective serotonin reuptake inhibitor antidepressants.", PHARMACOTHERAPY,, February 1999 (1999-02-01), pages 205 - 212, XP002118964 *
REDROBE J.P. ET AL: "Augmentation of antidepressant pharmacotherapy: A preclinical approach using the mouse forced swimming test.", CNS SPECTRUMS, (1999) 4/4 (73-81)., XP002118965 *
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, vol. 31, no. 3, 1 June 1997 (1997-06-01), pages 340 - 352, XP002066942 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7371756B2 (en) 1999-05-27 2008-05-13 Merck Patent Gmbh Use of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine and its physiologically acceptable salts
WO2000072832A3 (en) * 1999-05-27 2001-12-20 Merck Patent Gmbh Novel use of 1-[4-(cyanoindol-3yl)butyl]-4-(carbamoyl-benzofuran-5yl)-piperazine and its physiologically acceptable salts
EP1410800A1 (en) * 1999-05-27 2004-04-21 MERCK PATENT GmbH Use of 1- 4-(5-cyanoindol-3-yl)butyl -4-(2-carbamoylbenzofuran-5-yl)piperazine and its physiologically acceptable salts
WO2000072832A2 (en) * 1999-05-27 2000-12-07 Merck Patent Gmbh Novel use of 1-[4-(cyanoindol-3yl)butyl]-4-(carbamoyl-benzofuran-5yl)-piperazine and its physiologically acceptable salts
US6900212B1 (en) 1999-05-27 2005-05-31 Merck Patent Gmbh Use of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine and its physiologically acceptable salts
US7642261B2 (en) 1999-05-27 2010-01-05 Merck Patent Gmbh Use of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine and its physiologically acceptable salts
US7718705B1 (en) 1999-09-03 2010-05-18 Eli Lilly And Company Methods of using rapid-onset selective serotonin reuptake inhibitors for treating sexual dysfunction
JP2004522692A (en) * 2000-03-10 2004-07-29 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング Novel use of (R)-(-)-2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl] -chroman and its physiologically acceptable salts
JP4901046B2 (en) * 2000-03-10 2012-03-21 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング (R)-(-)-2- [5- (4-Fluorophenyl) -3-pyridylmethylaminomethyl] -chroman and novel uses of this physiologically acceptable salt
US7094786B2 (en) 2003-01-13 2006-08-22 Dynogen Pharmaceuticals, Inc. Method of treating nausea, vomiting, retching or any combination thereof
US7115606B2 (en) 2003-04-04 2006-10-03 Dynogen Pharmaceuticals, Inc. Method of treating lower urinary tract disorders
JP2008526700A (en) * 2004-12-30 2008-07-24 シュバルツ ファルマ アクチェンゲゼルシャフト Oxygen-containing phenyldiazepan carboxamides and cyclized phenyl piperazine carboxamides and use as dopamine D3 antagonists
CN113880815A (en) * 2020-07-03 2022-01-04 中国药科大学 Indole derivatives and preparation method and application thereof
CN113880815B (en) * 2020-07-03 2024-03-29 中国药科大学 Indole derivatives, preparation method and application thereof
US11977085B1 (en) 2023-09-05 2024-05-07 Elan Ehrlich Date rape drug detection device and method of using same

Also Published As

Publication number Publication date
FR2781671A1 (en) 2000-02-04
AU4916799A (en) 2000-02-21

Similar Documents

Publication Publication Date Title
EP1908461B1 (en) Use of (1S, 2R) enantiomer of milnacipran for the preparation of a medicine
AU2011234225B2 (en) Use of the phytocannabinoid cannabidivarin (CBDV) in the treatment of epilepsy
JP2010189432A (en) Supplement for metabolic dysfunction of brain
CA3144504A1 (en) Method of inducing dendritic and synaptic genesis in neurodegenerative chronic diseases
FR2851163A1 (en) USE OF DEXTROGYAN ENANTIOMER OF MILNACIPRAN FOR THE PREPARATION OF A MEDICINAL PRODUCT
JP2016166205A (en) Use of one or combination of phytocannabinoids in treatment of epilepsy
JP2005527599A (en) Use of zonisamide in obesity and eating disorders
WO2014055932A1 (en) Integrated neuromodulation system for mood enhancement of a living human subject
US20090203731A1 (en) Treatment of depression and other affective disorders
US9555055B2 (en) Use of albiflorin and metabolites thereof
EP1745786A1 (en) Neuroprotective compounds and pharmaceutical compositions comprising them
WO2000006160A1 (en) Treating depression with a combination of fluoxetine (prozac), pindolol (visken) and buspirone (buspar)
JP2891464B2 (en) Formulations for treating neurological diseases
US11376233B2 (en) Composition, containing sarpogrelate as active ingredient, for preventing or treating sensorineural hearing loss
WO2017157952A1 (en) Polycomplexes of poly-lysine compounds for preventing and/or combatting amyotrophic lateral sclerosis
WO1999013879A1 (en) Pharmaceutical compositions containing a monoamine oxydase inhibitor and their use in therapy
EP2435035A1 (en) Methods of enhancing selective serotonin reuptake inhibitor effects in mammals
EP1745785B1 (en) Pharmaceutical composition for preventing or treating cerebral oedema
WO2004062652A1 (en) Prevention and treatment of alzheimer&#39;s disease
WO2019072568A1 (en) Compound and composition for use in the preventive and/or curative treatment of diseases of the central nervous system characterised by a decline in neuronal plasticity, in particular characterised by a decline in synaptic plasticity
EP3624822B1 (en) Active agent comprising a mixture of poly-lysine compounds, and use in the treatment and prevention of post-stroke inflammation
CA2527145C (en) Use of iron for treating attention deficit hyperactivity disorder in children
JP6993480B2 (en) Composition for improving hearing function
US20050215644A1 (en) Methods for increasing neurotransmitter levels using hydroxycitric acid
Wajsbort et al. A comparative clinical investigation of the therapeutic effect of levodopa alone and in combination with a decarboxylase inhibitor (carbidopa) in cases of Parkinson's disease

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase