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WO2019073045A1 - Utilisation de donneurs de no - Google Patents

Utilisation de donneurs de no Download PDF

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Publication number
WO2019073045A1
WO2019073045A1 PCT/EP2018/077906 EP2018077906W WO2019073045A1 WO 2019073045 A1 WO2019073045 A1 WO 2019073045A1 EP 2018077906 W EP2018077906 W EP 2018077906W WO 2019073045 A1 WO2019073045 A1 WO 2019073045A1
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Prior art keywords
donor
disorders
depression
dose
group
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PCT/EP2018/077906
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English (en)
Inventor
Rudolf-Giesbert Alken
Alessia PERRONE
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BDD Berolina Drug Development GmbH
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BDD Berolina Drug Development GmbH
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Publication of WO2019073045A1 publication Critical patent/WO2019073045A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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 a novel use of NO donors, especially in form of a novel dose regimen, for treatment of psychotic disorders, depression, disorders, including neurodegenerative disorders, with comorbid psychosis or depression, and disorders with cognitive impairments and/or for the prevention of psychotic relapses and/or depressive relapses and/or suicidal attacks, as well as medicaments and a dosage regime for the use.
  • NO donors for treatment of cardiovascular diseases is well-known in the art and approved as medicinal products, e.g. sodium nitroprusside (SNP) in the use for immediate reduction of blood pressure, producing con- trolled hypotension to reduce bleeding during surgery and treatment of acute heart failure.
  • SNP sodium nitroprusside
  • nitric oxide synthases This is known to trigger an over-production of endogenous nitric oxide in the brain responsible of the formation of nitrite and nitrate and other Reactive Nitrogen Species (RNS), oxidative stress, nitrosylation of pro- teins, DNA damage and mitochondrial impairment.
  • NOS inhibitors have been tested in different models of animals for different diseases and have shown to successfully reduce the high brain levels of NO and to improve symptoms which are thought to be linked to abnormal NO concentrations.
  • NO donor which is a molecule that releases nitric oxide (NO exogenous supplementation) surprisingly acts on the NOS system in a comparable way as an NOS inhibitor: it is surprising to observe that a molecule which elevates the levels of nitric oxide with respect to baseline induces, contrary to what ex- pected, the same effect of an NOS inhibitor (more likely of a continuous administration of an NOS inhibitor).
  • a therapeutically effective amount of a NO donor insufficient to acutely lower mean arterial blood pressure or pulmonary artery pressure by more than 10% is aimed to treat different chronic diseases, among those also depression.
  • the therapeutic effects were observed by maintaining daily doses constant during the whole treatment.
  • An example in the clinics is a clinical trial in which a single 4 hr SNP infusion (0.5 mg/kg/min) has been tested in schizophrenic patients: immediate and long-lasting (over 4 weeks) significant improvements in psychotic symptoms, including negative and cognitive symptoms were observed.
  • Psychotic disorders like schizophrenia are complex chronic mental health disorders characterized by an array of symptoms, including delusions, hallucinations, disorganized speech or behaviour, and impaired cognitive ability. Thirty percent of patients with schizophrenia does not respond to antipsychotics, as well as subjects with neurodegenerative disorders or other pa- thologies with associated psychosis do not respond well or do not respond at all to the conventional antipsychotics.
  • the present invention relates to the novel use of NO donors, especially in form of a novel dose regimen, including but not restricted to nitroglycerin, molsidomine, ISMN, ISDN and sodium nitroprusside, at convenient and new routes of administration, at weekly doses less than 10% of the NO donors when used for approved cardiovascular indications, which provides enhancement of the efficacy of known anti-psychotics and known antidepres- sants in the treatment for psychotic disorders, depression and disorders with cognitive impairments, without exhibiting direct central and peripheral cardiovascular effects.
  • a novel dose regimen including but not restricted to nitroglycerin, molsidomine, ISMN, ISDN and sodium nitroprusside, at convenient and new routes of administration, at weekly doses less than 10% of the NO donors when used for approved cardiovascular indications, which provides enhancement of the efficacy of known anti-psychotics and known antidepres- sants in the treatment for psychotic disorders, depression and disorders with cognitive impairments, without exhibiting direct central and peripheral cardiovascular effects.
  • the present invention relates also to a new treatment schedule combining single supra-threshold dose of the NO donors followed by a substantial NO donor free period in order to make use of its immediate neuropharmacologi- cal effect and provides its long-lasting duration.
  • the present invention relates also to the novel use of the NO donors and provides a monotherapy or a combination therapy with lower doses of the known anti-psychotics and anti-depressants with the aim of improving and enhancing the effect, shorten the time to the full therapeutic effect and reducing the side effects.
  • One object of the present invention is the novel use of the NO donors wherein psychotic disorders, depression, disorders with comorbid depression, and disorders with cognitive impairments are selected.
  • Another object of the present invention is the novel use of NO donors prefer- ably consisting of sodium nitroprusside (SNP), molsidomine, isosorbide mononitrate (ISMN), isosorbide dinitrate (ISDN) and nitroglycerine (GTN).
  • SNP sodium nitroprusside
  • ISMN isosorbide mononitrate
  • ISDN isosorbide dinitrate
  • GTN nitroglycerine
  • a further object of the present invention is the novel use of the NO donors wherein the neuropsychiatric diseases are selected from the group of schizo- phrenia, treatment-resistant schizophrenia and bipolar disorder where both positive, negative symptoms and cognitive deficits are targeted, including psychotic disorders during neurodegenerative diseases like Parkinson's Disease and Alzheimer's Disease.
  • the neuropsychiatric diseases are selected from the group of schizo- phrenia, treatment-resistant schizophrenia and bipolar disorder where both positive, negative symptoms and cognitive deficits are targeted, including psychotic disorders during neurodegenerative diseases like Parkinson's Disease and Alzheimer's Disease.
  • depression is selected from the group of patients suffering of Major Depression, general depressive disorders, treatment-resistant depression, such as secondary and reactive depression, suicidal attacks, and diseases with comorbid depression, including depressive symptoms during neurodegenerative diseases like Parkinson's Disease and Alzheimer's Disease.
  • Still another object of the present invention is the novel use of the NO donors wherein the comorbid depression is present in patients suffering from peripheral and central cancers, celiac disease, hereditable fructose intolerance (HFI) and fructose malabsorption, diabetes, irritable bowel syndrome (IBS), cardiovascular diseases, neuro-inflammatory disorders, neurodegenerative diseases, including M. Parkinson and Alzheimer's disease, neuropsychiatric diseases, panic and anxiety disorders.
  • HFI hereditable fructose intolerance
  • IBS irritable bowel syndrome
  • cardiovascular diseases include M. Parkinson and Alzheimer's disease, neuropsychiatric diseases, panic and anxiety disorders.
  • disorders with cognitive impairments are selected from the group of neuropsychiatric diseases, selected from the group of schizophrenia and bipolar disorder, depression and neurodegenerative diseases selected from the group, comprising Alzheimer's disease, Parkinson's disease, frontotem- poral degeneration, Lewy Body disease, corticobasal degeneration, Hunting- ton's disease, PSP, vascular dementia, and/or wherein the neuropsychiatric disease is selected from the group comprising schizophrenia and bipolar disorders.
  • Still another object of the present invention is the novel use of NO donors wherein the prevention of psychotic and/or depressive relapses and/or suicidal attacks is selected.
  • a further object of the present invention is the proposed NO donor treatment schedule (using single doses) shifts the dose-response curve of anti- psychotic and/or anti-depressant treatment to the left leading to better tolerated doses of the antipsychotic and/or antidepressant treatment.
  • a further object of the present invention is the proposed NO donor treatment schedule (using single doses) reduces the time to full response of anti- psychotic and/or anti-depressant treatment to less than 3 days.
  • the appropriate single dose of the NO donor has to exhibit a transient increase in the brain NO level for 10 nM or more.
  • the brain nitric oxide response after 1 .5 mg/kg i.p. SNP elevated the brain NO concentration for more than 10 nM and resulted in the augmentation of the risperidone effect in the conditioned avoidance response test, a test with high predictive value for antipsychotic relevant effects.
  • An object of the present invention is also to provide preferred routes of administration, among those nasal or buccal nitroglycerin, oral or nasal molsidomine, nasal or buccal ISMN or ISDN, as well as other established routes for the NO donors.
  • compositions comprising at least one NO donor.
  • the composition may comprise usual pharmaceutical compo- sitions for the above-named application pathways.
  • Still another object of the present invention is a composition
  • a composition comprising at least one NO donor and at least one of the further ingredients selected from the group of anti-psychotics selected from the groups of phenothiazines, bu- tyrophenone derivatives, indole derivatives, thioxanthene derivatives, diphe- nylbutylpiperidine derivatives, diazepines, axazepines, thiazepines and ox- epines, and benzamides;
  • anti-depressants selected from the groups of DOPA decarboxylase inhibitors, catechol-O-methyltransferase inhibitors, selective and non-selective mono- amine oxidase (MAO) and monoamine-A oxidase (MAO-A) inhibitors,
  • NADPH-cytochrome CYP450 reductase (CPR) inhibitors conventional antidepressants (SSRIs), atypical antidepressants (including SNRIs), psycholep- tics, nonsteroidal anti-inflammatory drugs, NMDA receptor antagonists, NMDAr partial agonists, glucocorticoid receptor antagonists, serotonin 5HT1A partial agonists and 5HT 2 antagonists, lithium, COX-inhibitors;
  • PDE phosphodiesterase
  • Still a further object of the present invention is to provide a monotherapy of single NO donors, repeated after 3 to 14 days in order to prevent relapses of psychotic/depressive episodes or suicidal attacks.
  • One object of the present invention is a NO donor for use in the treatment of psychotic disorders, depression, neurodegenerative disorders with comorbid psychosis or comorbid depression, or disorders with cognitive impairments or for prevention of psychotic relapses and/or depressive relapses and/or suicidal attacks.
  • the application of the NO donor in the treatment is performed by the application of NO donor in a pulsatile regime.
  • pulsatile is defined above and the pulsatile treatment of a subject with an NO donor is an essential feature of the present invention.
  • the NO donor is applied in a dose that is lower than the dose used for cardiovascular indications. It is also an essential feature of the present invention that the treatment with an NO donor in the sense of the present invention shall not affect the cardiovascular system of the subject that is treated according to the novel use of the known NO donors. The novel use of the NO donors shall have an effect to the brain of the subject under medication and not on the cardiovascular system.
  • the NO donor is applied in a dose that is less than 20% lower than the dose used for cardiovascular indications, preferred less than 15% lower, more preferred less than 10% lower, and most preferred less than 5% lower.
  • the NO donor is applied in a dose that is able to induce an increase of exogenous nitric oxide in the brain of at least 8 nM, established to be lowest threshold for the therapeutic effect of the NO donor.
  • the NO donor is applied in a dose with a drug free interval in a range from 3 to 30 days, pre- ferred from 1 to 2 weeks, more preferred from 2 to 3 weeks and most preferred from 3 to more than 4 weeks.
  • the pulsatile application of the NO donor is a preferred feature. Pulsatile in the sense of the present application means also that a longer period of non- medication is advantageous for the novel use of NO donors according to the present invention.
  • a preferred use according to the invention is also that the NO donor is administered orally, buccally, respiratorally, parenterally or with intravenous infusion.
  • the type of application depends on the NO donor that is used according to the invention.
  • the appropriate application path is generally known in the art.
  • the NO donor is administered through intravenous infusion where the infusion period ranges from 30 minutes to 4 hours, preferably from 30 minutes to 1 hour.
  • the NO donor is selected from enzymatic NO donors or non-enzymatic NO donors or a combination thereof. It is especially preferred according to the present invention that the enzymatic
  • NO donor is selected from the group consisting of sodium nitroprusside and molsidomine and a combination thereof.
  • non- enzymatic NO donor is selected from the group consisting of isosorbide dini- trate, isosorbide mononitrate, nitroglycerine, amyl nitride and nitropenta and a combination thereof.
  • Preferred according to the present invention is also that the treatment in form of the novel use of NO donors is performed for psychotic disorders are selected from the group consisting of schizophrenia, treatment-resistant schizophrenia and bipolar disorder where both positive, negative symptoms and cognitive deficits are targeted.
  • psychotic disorders are selected from the group consisting of schizophrenia, treatment-resistant schizophrenia and bipolar disorder where both positive, negative symptoms and cognitive deficits are targeted.
  • depressions are selected from the group consisting of Major Depression, general depressive disorders, treatment-resistant depression, such as secondary and reactive depression, suicidal attacks, and diseases with comorbid depression.
  • comorbid depressions are selected from the group consisting of peripheral and central cancers, celiac disease, hereditable fructose intolerance (HFI) and fructose malabsorption, diabetes, irritable bowel syndrome (IBS), cardiovascular diseases, neuro-inflammatory disorders, neurodegenerative diseases, including M. Parkinson and Alzheimer's disease, neuropsychiatric diseases, panic and anxiety disorders.
  • cognitive impairments are selected from the group of neuropsychiatric diseases, se- lected from the group of schizophrenia and bipolar disorder, depression and neurodegenerative diseases selected from the group, comprising Alzheimer's disease, Parkinson's disease, frontotemporal degeneration, Lewy Body disease, corticobasal degeneration, Huntington's disease, PSP, vascular dementia, and/or wherein the neuropsychiatric disease is selected from the group comprising schizophrenia and bipolar disorders.
  • the NO donor is used in combination with a further medicament that is suitable for treatment of psychotic disorders, depression, neurodegenerative disorders with comor- bid psychosis or comorbid depression, or disorders with cognitive impairments or for prevention of psychotic relapses and/or depressive relapses and/or suicidal attacks.
  • a further medicament that is suitable for treatment of psychotic disorders, depression, neurodegenerative disorders with comor- bid psychosis or comorbid depression, or disorders with cognitive impairments or for prevention of psychotic relapses and/or depressive relapses and/or suicidal attacks.
  • the further medicament is selected from anti-psychotics, selected from the group comprising phenothiazines, butyrophenone derivatives, indole derivatives, thioxanthene derivatives, diphenylbutylpiperidine derivatives, di- azepines, axazepines, thiazepines, oxepines, and benzamides
  • anti-psychotics selected from the group comprising phenothiazines, butyrophenone derivatives, indole derivatives, thioxanthene derivatives, diphenylbutylpiperidine derivatives, di- azepines, axazepines, thiazepines, oxepines, and benzamides
  • the further medicament is selected from anti-depressants selected from the group comprising DOPA decarboxylase inhibitors, catechol-O- methy transferase inhibitors, selective and non-selective monoamine oxidase (MAO) and monoamine-A oxidase (MAO-A) inhibitors, NAD PH -cytochrome CYP450 reductase (CPR) inhibitors, conventional antidepressants (SSRIs), atypical antidepressants (including SNRIs), psycholeptics, nonsteroidal antiinflammatory drugs, NMDA receptor antagonists, NMDAr partial agonists, glucocorticoid receptor antagonists, serotonin 5HTi A partial agonists and 5HT 2 antagonists, lithium, and COX-inhibitors;
  • anti-depressants selected from the group comprising DOPA decarboxylase inhibitors, catechol-O- methy transferase inhibitors, selective and non-selective monoamine oxidase (MAO
  • the further medicament is selected from phosphodiesterase (PDE) inhibitors selected from those able to target both the cGMP and cAMP signal transduction cascades
  • PDE phosphodiesterase
  • the further medicament is administered with lower doses than those generally used. It has been found that the additional use of NO donors increases the efficiency of the effect of the drugs and medicaments already use by a subject that underlies a certain medication. This means that the amount of the further medicaments can be reduced, without reducing the effect of the further medicament. In that respect, the lower dose or amounts reduce side-effects of the drugs and have an positive impact on the metabolism in the body of the subject.
  • the dose of the further medicament is a sub-effective dose of the further medicament as it is used in the medication that is usual for the further medicament in the treatment where the further medicament is applied for.
  • One object of the present invention is also that the NO donor is applied in form of a monotherapy in a dose, wherein the NO donor is applied in a dose that is less than 20% lower than the dose used for cardiovascular indications, preferred less than 15% lower, more preferred less than 10% lower, and most preferred less than 5% lower, is repeated after 3 to 14 days, for the prevention of psychotic relapses and/or depressive relapses and/or suicidal attacks. It has been found that subjects underlying psychotic relapses and/or depressive relapses and/or suicidal attacks can be prevented from those affects, when the novel use of the NO donors is provided and applied to those subjects. This means that with a monotherapy of low doses of NO donors psychotic relapses and/or depressive relapses and/or suicidal attacks can be prevented. This is a great advantage of the present invention.
  • a further object of the present invention is to provide a pharmaceutical prepa- ration, comprising at least one NO donor, wherein the pharmaceutical preparation is in form of a tablet, a buccal tablet, an injection solution, an infusion solution, an inhalation preparation, an intranasal spray, or any other suitable galenic form for the application of NO donors, and wherein the amount of the active ingredient is lower than the amount used for cardiovascular indica- tions.
  • Fig. 1 shows the time curve of NO levels in nucleus accumbens (NAc) in rat brains after sodium nitroprusside application;
  • Fig. 2 shows the time curve of NO levels in the prefrontal cortex (PFC) in rat brains after sodium nitroprusside application;
  • Fig. 3. shows the suppression of conditioned avoidance response (% avoidance) in CAR rats model for risperidone (sub-effective dose of 0,25 mg/kg) and sodium nitroprusside (1 , 1 ,5, 2 mg/kg) after 20 minutes post-dose;
  • Fig. 4 shows the time curve of NO levels in nucleus accumbens (NAc) in rat brains after nitroglycerine (10 mg/mg i.p.) application;
  • Fig. 5. shows the suppression of conditioned avoidance response (% avoid- ance) in CAR rats model for risperidone (sub-effective dose of 0,25 mg/kg) and nitroglycerine (10 mg/kg) after 20 minutes post-dose.
  • NO donors are, in the sense of the present invention, chemical compounds that induce the formation of exogenous nitric oxide in the brain of the subjects treated with NO donors.
  • NO donors known in the art are sodium nitro- prusside (SNP), molsidomine, isosorbide dinitrate (ISDN), isosorbide mononitrate (ISMN), nitroglycerine, amyl nitride, nitropenta and the like.
  • NO donors are used in a novel treatment.
  • a special feature of the novel treatment is the "pulsatile" application of NO donors.
  • the term “pulsatile” means in the sense of the present invention that NO donors are not applied in a continuous way during a long time period.
  • the application may be repeated after the period of non-medication with NO donors.
  • the term “pulsatile” describes also that the application may be performed continuously over a long time period, but not in a continuous way of permanent application but in a way of repeated applications of NO donors.
  • the term “pulsatile” is therefore in contrast to continuous applications as they are performed in general medication of medicaments in order to build up a constant blood level of the respective medicament.
  • the "pulsatile” treatment causes short term increases of NO levels, especially in the brain, which triggers the reaction in the brain.
  • treatment describes, in the sense of the present invention, a method for applying a medicament to a subject being in need of such medication.
  • the method of "treatment”, according to the present invention may comprise a monotherapy or a combination therapy with at least two medicaments.
  • the treatment in form of a monotherapy refers to the use of a NO donor only, without further medication with anti-psychotics or anti-depressants or other medicaments suitable for the treatment of psychotic disorders, depression, neurodegenerative disorders with comorbid psychosis or comorbid depression, or disorders with cognitive impairments or for prevention of psychotic relapses and/or depressive relapses and/or suicidal attacks.
  • treatment refers also to a combination therapy with a NO donor and anti-psychotics or antidepressants or other medicaments suitable for the treatment of psychotic disorders, depression, neurodegenerative disorders with comorbid psychosis or comorbid depression, or disorders with cognitive impairments or for prevention of psychotic relapses and/or depressive relapses and/or suicidal attacks.
  • the present invention relates to the surprising therapeutic effect of a pulsatile treatment of an NO donor like nitroglycerine, molsidomine, ISMN, ISDN and sodium nitroprusside on both psychotic and negative symptoms, as well as on cognitive impairments.
  • the surprising and innovative issue of the pulsatile treatment of an NO donor relates to the possibility of administering the NO donor with a drug free interval between one administration and the following of at least three days (extended up to more than 4 weeks) in order for the NO donor to be therapeutically effective, avoiding in this way a continuous daily treatment, as in the case of the U. S. patent 6,472,390 B.
  • a dose of NO donor is able to induce the aimed therapeutic effects when the brain peak concentration of exogenous nitric oxide reaches at least a threshold of 8 - 10 nM over baseline.
  • the present invention claims that a reduction of the infusion period from the 4 hours, as known in the art, to 30 minutes to 1 hour SNP surprisingly induces therapeutic effects in neuropsychiatric disorders in the same order of magnitude.
  • the uniqueness of the present invention relates to the novel dose regimen of the NO donors like nitroglycerine, molsidomine, ISMN, ISDN and sodium nitroprusside, characterized by 1 ) an administration dose defined according to the nitric oxide peak concentration reached in the brain and es- tablished to be over a precise threshold value (8 nM) for a minimum duration of 20 min in order for the NO donor to be therapeutic effective via various routes of administration including orally, buccally, respiratorally, parenterally or intravenous infusion, 2) a pulsatile treatment with a drug free interval es- tablished to be in a range from 3 to 30 days, preferably from 1 to 4 weeks, more preferably from 2 to 3 weeks, 3) an infusion period of 30 minutes - 1 hour for those NO donors administered through intravenous infusion.
  • the present invention relates to the novel use of the NO donors like nitroglycerine, molsidomine, sodium nitroprusside, ISMN and ISDN and others for the treatment of psychotic disorders, depression, disorders, including neurodegenerative disorders, with comorbid psychosis or depression, and disorders with cognitive impairments, as well as medicaments and a dosage regime for the use.
  • NO donors like nitroglycerine, molsidomine, sodium nitroprusside, ISMN and ISDN and others for the treatment of psychotic disorders, depression, disorders, including neurodegenerative disorders, with comorbid psychosis or depression, and disorders with cognitive impairments, as well as medicaments and a dosage regime for the use.
  • a further object of the present invention is also a pharmaceutical preparation comprising at least one NO donor, wherein the pharmaceutical preparation is in form of a tablet, a buccal tablet, an injection solution, an infusion solution, an inhalation preparation, an intranasal spray, or any other suitable galenic form for the application of NO donors, and wherein the amount of the active ingredient is lower than the amount used for cardiovascular indications.
  • compositions containing NO donors for cardiovascular indications are well known in the art. But, according to the invention, the novel use of NO donors for the treatment of psychotic disorders, depression, neurodegenerative disorders with comorbid psychosis or comorbid depression, or disorders with cognitive impairments or for prevention of psychotic relapses and/or depressive relapses and/or suicidal attacks, is performed with a dose of the NO donor, wherein the dose is lower that the dose suitable for cardio- vascular indications.
  • the novel treatment according to the invention shall not affect the cardiovascular system of the subject to be treated it is neces- sary to provide a pharmaceutical preparation with lower amounts of the active ingredient, namely the NO donors.
  • SNP sodium nitroprusside
  • SNP caused in rat a rapid increase in NO levels that lasted for approximately 30 minutes in both nucleus accumbens (NAc), shown in Figure 1 , and pre- frontal cortex (PFC), shown in Figure 2.
  • NAc nucleus accumbens
  • PFC pre- frontal cortex
  • Risperidone 0.25 mg/kg alone showed a 20% suppression of CAR, which is far below the degree of CAR suppression required for a significant clinical antipsychotic effect in schizophrenia, which is 70-80%.
  • Addition of SNP 1 , 1 .5 and 2 mg/kg to risperidone dramatically enhanced the antipsychotic-like effect of risperidone.
  • addition of the highest dose of SNP i.e 2 mg/kg, resulted in escape failures which could indicate risk of non-specific side effects. Only SNP 2 mg/kg given alone generated a small, but significant suppression of CAR.
  • nitroglycerine (10 mg/kg, i.p.) was measured in the CAR model after 20 minutes from injection. The results are shown in Figure 5.
  • the CAR test is a highly predictable test for clinically effective antipsychotic drugs.
  • a 25-year-old Caucasian male with schizophrenia was treated with a single dose of an intranasal spray of nitroglycerine, 0.3 mg per shot.
  • the patient was under treatment of risperidone.
  • the patient showed immediate improvements in positive and negative psychotic symptoms as well as in cognition which lasted for a period of three weeks.
  • a 58-year-old Caucasian female with Alzheimer ' s Disease was treated with one single shot (1 .25 mg) of intranasal spray of ISDN. Improvements of both memory and cognition lasted for three weeks from the administration.

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Abstract

L'invention concerne une nouvelle utilisation de donneurs de NO, en particulier sous la forme d'un nouveau schéma posologique, pour le traitement de troubles psychotiques, de la dépression, de troubles, comprenant des troubles neurodégénératifs, avec une psychose ou une dépression comorbides, et des troubles avec des déficiences cognitives et/ou pour la prévention de rechutes de psychoses et/ou de rechutes de dépressions et/ou d'attaques suicidaires, ainsi que des médicaments et un schéma posologique destinés à être utilisés à cette fin.
PCT/EP2018/077906 2017-10-12 2018-10-12 Utilisation de donneurs de no Ceased WO2019073045A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6472390B1 (en) 2001-11-13 2002-10-29 Duke University Use of therapeutic dosages for nitric oxide donors which do not significantly lower blood pressure or pulmonary artery pressure
WO2011143755A1 (fr) * 2010-05-21 2011-11-24 Serdar Dursun Compositions et procédés de traitement de la schizophrénie

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6472390B1 (en) 2001-11-13 2002-10-29 Duke University Use of therapeutic dosages for nitric oxide donors which do not significantly lower blood pressure or pulmonary artery pressure
WO2011143755A1 (fr) * 2010-05-21 2011-11-24 Serdar Dursun Compositions et procédés de traitement de la schizophrénie

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