[go: up one dir, main page]

WO2011143755A1 - Compositions et procédés de traitement de la schizophrénie - Google Patents

Compositions et procédés de traitement de la schizophrénie Download PDF

Info

Publication number
WO2011143755A1
WO2011143755A1 PCT/CA2011/000581 CA2011000581W WO2011143755A1 WO 2011143755 A1 WO2011143755 A1 WO 2011143755A1 CA 2011000581 W CA2011000581 W CA 2011000581W WO 2011143755 A1 WO2011143755 A1 WO 2011143755A1
Authority
WO
WIPO (PCT)
Prior art keywords
donor
antipsychotic drug
drug
schizophrenia
pharmaceutical composition
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CA2011/000581
Other languages
English (en)
Inventor
Serdar Dursun
Jamie E. C. Hallak
Glen B. Baker
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of WO2011143755A1 publication Critical patent/WO2011143755A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4515—Non condensed piperidines, e.g. piperocaine having a butyrophenone group in position 1, e.g. haloperidol
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • 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
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the field of the invention generally relates to compositions and methods of treatment of schizophrenia.
  • Schizophrenia is a serious human disease, yet its aetiology and pathophysiology remain largely unknown.
  • Antipsychotic medications have been available for a number of years, and include typical and atypical antipsychotic medications.
  • Typical antipsychotic drugs include chlorpromazine, emonopride, fluphenazine, haloperidol, loxapine, mesoridazine, molindone, pimozide, perphenazine, raclopride, remoxipride, spiperone, thioridazine, thiothixene, and trifluoperazine.
  • Side effects of such typical antipsychotic drugs can include extrapyramidal side effects, such as rigidity, persistent muscle spasms, tremors, restlessness, and tardive dyskinesia.
  • Atypical antipsychotics exhibit a different and recognizable clinical and pharmacological profile relative to typical antipsychotics and exhibit advantages over the typical antipsychotics.
  • Examples of atypical antipsychotics include asenapine, olanzapine, clozapine, risperidone, sertindole, quetiapine, aripiprazole, amisulpride, ziprasidone, and paliperidone.
  • Atypical antipsychotics generally exhibit greater efficacy in the treatment of overall psychopathology in schizophrenic patients nonresponsive to typical antipsychotics. Although atypical antipsychotics can be effective in treating the positive symptoms of schizophrenia and produce fewer extrapyramidal effects, atypical antipsychotics can also increase the risk of diabetes and high cholesterol, produce marked weight gain, and in some cases may produce serious side effects such as agranulocytosis. While in some respects atypical antipsychotics represent a improvement over typical antipsychotics, cognitive and psychological deficits continue to persist in many schizophrenia patients treated with atypical antipsychotic drugs.
  • compositions and methods for the treatment of schizophrenia in a patient are provided.
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a nitric oxide (NO) donor for treatment of a patient with schizophrenia.
  • NO nitric oxide
  • a method for treating schizophrenia in a patient in need thereof comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a NO donor.
  • a pharmaceutical composition comprising a therapeutically effective amount of a NO donor for treating schizophrenia in a patient in need thereof.
  • a pharmaceutical composition comprising a therapeutically effective amount of a NO donor in the manufacture of a medicament for treating schizophrenia in a patient in need thereof.
  • kits for treating schizophrenia in a patient in need thereof comprising: a pharmaceutical composition comprising a therapeutically effective amount of a NO donor; and instructions for the use thereof.
  • a pharmaceutical composition for administration to a patient comprising an effective amount of a NO donor for treating positive symptoms, negative symptoms and/or cognitive symptoms of schizophrenia in said patient.
  • a method of treating schizophrenia in a patient comprising: administering to said patient an effective amount of a NO donor for treating positive symptoms, negative symptoms and/or cognitive symptoms of schizophrenia in said patient.
  • said patient is a male or female patient with schizophrenia.
  • administration is an infusion over four hours.
  • said NO donor is sodium nitroprusside (SNP).
  • NPS is administered to said patient as an infusion of 0 ⁇ g/kg/hour over four hours.
  • Figure 1 depicts line graphs illustrating physiologic measurements
  • Figure 2 depicts line graphs illustrating Brief Psychiatric Rating Scale (BPRS) ratings during the first twelve hours (Panel A) and from day one until the end of the experiment (Panel B);
  • BPRS Brief Psychiatric Rating Scale
  • Figure 3 depicts line graphs illustrating BPRS subscale ratings during the full experiment
  • Figure 4 depicts bar graphs illustrating BPRS thinking disorder subscales measured at baseline and week 4, empty columns represent the SNP group, and hatched columns represent the PLB group);
  • Figure 5 depicts line graphs illustrating Positive and Negative Syndrome Scale (PANSS) negative subscale ratings during the first twelve hours (Panel A) and from day one until week 4 (Panel B).
  • PANSS Positive and Negative Syndrome Scale
  • the present invention relates to a composition(s) and method(s) for the treatment of schizophrenia in a patient.
  • a nitric oxide (NO) donor is used for the treatment of schizophrenia in a patient.
  • sodium nitroprusside is used for the treatment of schizophrenia in a patient.
  • Schizophrenia refers to a group of neuropsychiatric disorders characterized by dysfunctions of the thinking process, such as delusions, hallucinations, and extensive withdrawal of the patient's interests from other people. Schizophrenia includes the subtypes of paranoid schizophrenia characterized by a preoccupation with delusions or auditory hallucinations, hebephrenic or disorganized schizophrenia characterized by disorganized speech, disorganized behavior, and flat or inappropriate emotions; catatonic schizophrenia dominated by physical symptoms such as immobility, excessive motor activity, or the assumption of strange postures; undifferentiated schizophrenia characterized by a combination of symptoms characteristic of the other subtypes; and residual schizophrenia in which a person is not currently suffering from positive symptoms but manifests negative and/or cognitive symptoms of schizophrenia (The Diagnostic and Statistical Manual of Mental Disorders )
  • schizophrenia also includes and other closely associated psychotic disorders such as schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder, and unspecified psychotic disorders.
  • Schizoaffective disorder characterized by symptoms of schizophrenia as well as mood disorder such as major depression, bipolar mania, or mixed mania, is included as a subtype of schizophrenia .
  • schizophrenia also includes conditions related to schizophrenia and may include, but are not limited to: schizoaffective disorder, schizotypal personality disorder, schizotypy, and atypical psychotic disorders.
  • patient refers to animals, preferably mammals, more preferably humans.
  • patient includes adults and children, and includes men and women.
  • children includes neonates, infants, and adolescents.
  • the human male or female patient is between 19 and 40 years of age.
  • the human male or female patient is 19 years of age or less.
  • the human male or female patient is 40 years of age of more.
  • the patient is within their first five years of disease.
  • therapeutic benefit includes eradication or amelioration of the underlying disorder or condition being treated.
  • therapeutic benefit includes alleviation or partial and/or complete halting of the progression of the disease, or partial or complete reversal of the disease.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological or psychological symptoms associated with the underlying condition, either on a temporary or permanent basis, such that an improvement is observed in the patient, notwithstanding the fact that the patient is still affected by the condition.
  • a prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition, or decreasing the likelihood of occurrence of a condition.
  • “treat”, “treating” or “treatment” includes prophylaxis.
  • the patient has previously been treated with an antipsychotic drug.
  • the patient has previously been treated with a typical antipsychotic drug.
  • the patient has previously been treated with an atypical antipsychotic drug.
  • Schizophrenia symptoms can be classified as positive, negative, or cognitive.
  • Positive symptoms of schizophrenia can include delusions and hallucinations, which can be measured using, for example, the Positive and Negative Syndrome Scale (PANSS) negative subscale.
  • Negative symptoms of schizophrenia include affect blunting, anergia, alogia, and social withdrawal, which can be measured for example, using the Scales for the Assessment of Negative Symptoms (SANS).
  • Cognitive symptoms of schizophrenia include impairment in obtaining, organizing, and using intellectual knowledge which can be measured using the Positive and Negative Syndrome Scale-cognitive subscale (PANSS-cognitive subscale), by assessing the ability to perform cognitive tasks such as, for example, using the Wisconsin Card Sorting Test, the Stroop Color Word Test (SCWT), a verbal fluency task (FAS) and a continuous performance test (the N-back task) as proposed by Liddle and Morris 15
  • PANSS-cognitive subscale Positive and Negative Syndrome Scale-cognitive subscale
  • treatment results in improved positive, negative, and/or cognitive symptoms of schizophrenia.
  • composition(s) and method(s) of the present invention result in improved positive, negative and cognitive symptoms of schizophrenia in a patient.
  • administration of a NO donor improves the positive, negative, or cognitive symptoms of schizophrenia, or combinations thereof.
  • an effective amount of SNP is used in the treatment of schizophrenia in a patient.
  • intravenous administration of SNP improved the positive, negative and cognitive symptoms of schizophrenia and the therapeutic benefit was maintained over four weeks.
  • an effective amount of the nitric oxide (NO) donor sodium nitroprusside (e.g., Nipride®) is used in the treatment of a patient.
  • the NO donor can include a variety of NO donors including, but not limited to, for example, organic NO donors, inorganic NO donors and prodrug forms of NO donors.
  • Additional suitable NO donors include compounds that can be metabolized in vivo into a compound which delivers NO (e.g., a prodrug form of a NO donor; a NO- releasing drug such as a NO-releasing non-steroidal anti-inflammatory drug (NO- NSAIDs), examples of which include nitro-aspirin, NCX 4016, nitro-(flurbiprofen), HCT 1026, NCX 2216; or a binary NO generating system, such as acidified nitrates), or compounds that serve as physiological precursor of nitric oxide, such as L-arginine and salts of L-arginine.
  • NO- NSAIDs NO-releasing non-steroidal anti-inflammatory drug
  • the NO donor may include at least one organic nitrate (including esters of nitric acid) and can be either a cyclic or acyclic compound.
  • NO donors include nitroglycerin (NTG), isosorbide dinitrate (ISDN), isosorbide mononitrate (ISMN) which may include isosorbide-2-mononitrate (IS2N) and/or isosorbide-5- mononitrate (IS5N), erythrityl tetranitrate (ETN), pentaerythritol tetranitrate (PETN), ethylene glycol dinitrate, isopropyl nitrate, glyceryl- 1 -mononitrate; glyceryl- 1 ,2-dinitrate, glyceryl-l,3-dinitrate, butane- 1,2,4-triol trinitrate, and the like.
  • Nitroglycerin and other organic nitrates including ISDN, ETN, and PETN have been given regulatory approval for use in treatments in other fields of medicine on human subjects.
  • Additional NO donors include sodium nitroprusside (SNP), N,0-diacetyl-N-hydroxy-4- chlorobenzenesulfonamide, NG-hydroxy-L-arginine (NOHA), hydroxyguanidine sulfate, molsidomine, 3-mo holinosydnonimine (SIN-1), ( ⁇ )-S-nitroso-N-acetylpenicillamine (SNAP), S-nitrosoglutathione (GSNO), ( ⁇ )-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3- hexeneamide (FK409), ( ⁇ )-N- [(E)-4-ethyl-3 - [(Z)-hydroxyimino] -5-nitro-3 -hexen- 1 -
  • the NO donor is a NO mimetic compound.
  • compounds that interfere with the breakdown of NO in vivo may be administered.
  • an effective amount refers to an amount sufficient to effect beneficial or desired clinical results.
  • An effective amount can be administered in one or more administrations.
  • an effective amount is an amount that is sufficient to demonstrate improved positive, negative and/or cognitive symptoms of schizophrenia in a patient.
  • the improvement is demonstrated over four weeks. In another example, the improvement is demonstrated for a period greater than four weeks.
  • treatment with SNP in a patient results in improved positive, negative and/or cognitive symptoms of schizophrenia.
  • the improvement is demonstrated over four weeks. In another example, the improvement is demonstrated over a period greater than four weeks.
  • the NO donor composition(s), e.g., pharmaceutical compositions, can be administered to the patient by a variety of, or a combination, of several routes, such as oral, intravenous, trans-mucosal (e.g., nasal, vaginal, etc.), pulmonary, transdermal, ocular, buccal, sublingual, intraperitoneal, intrathecal, intramuscular.
  • Solid compositions for oral administration can contain suitable carriers or excipients, such as corn starch, gelatin, lactose, acacia, sucrose, macrocrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, lipids, alginic acid, or ingredients for controlled slow release.
  • Disintegrators that can be used include, without limitation, micro-crystalline cellulose, corn starch, sodium starch glycolate and alginic acid.
  • Tablet binders that may be used include, without limitation, acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch, and ethylcellulose.
  • Liquid compositions for oral administration prepared in water or other aqueous vehicles can include solutions, emulsions, syrups, and elixirs containing, together with the active compound(s), wetting agents, sweeteners, coloring agents, and flavoring agents.
  • Various liquid and powder compositions can be prepared by conventional methods for inhalation into the lungs of the patient to be treated.
  • Compositions that are injected may contain various carriers such as vegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, polyols (glycerol, propylene glycol, liquid polyethylene glycol, and the like).
  • the compounds may be administered by the drip method, whereby a pharmaceutical composition containing the active compound(s) and a physiologically acceptable excipient is infused.
  • Physiologically acceptable excipients may include, for example, 5% dextrose, 0.9% saline, Ringer's solution or other suitable excipients.
  • a sterile composition of a suitable soluble salt form of the compound can be dissolved and administered in a pharmaceutical excipient such as Water-for-Injection, 0.9% saline, or 5% glucose solution, or depot forms of the compounds (e.g., decanoate, palmitate, undecylenic, enanthate) can be dissolved in sesame oil.
  • a pharmaceutical excipient such as Water-for-Injection, 0.9% saline, or 5% glucose solution
  • depot forms of the compounds e.g., decanoate, palmitate, undecylenic, enanthate
  • the pharmaceutical composition can be formulated as a chewing gum, lollipop, or the like.
  • SNP is administered as an infusion of 0 ⁇ g/kg/hour over four hours.
  • combination therapies wherein two therapeutic compounds are used for treating a patient with schizophrenia.
  • Combined therapy may include, and is not limited to, substantially concomitant administration, sequential administration, administration at fixed intervals, and the like.
  • a patient with schizophrenia is treated with an antipsychotic drug approved for use in humans and an NO donor.
  • a patient with schizophrenia is treated with an antipsychotic drug approved for use in humans and SNP.
  • Antipsychotic drugs used in the treatment of schizophrenia are known and include a wide variety of typical and a typical antipsychotic agents.
  • the antipsychotic compounds may be administered sequentially or concurrently with the NO donor compositions described herein.
  • the concurrently administered compounds may be administered to the subject separately or may be formulated together.
  • Typical antipsychotic drugs include, but are not limited to, chlorpromazine, emonopride, fluphenazine, haloperidol, loxapine, mesoridazine, molindone, pimozide, perphenazine, raclopride, remoxipride, spiperone, thioridazine, thiothixene, and trifluoperazine.
  • Side effects of such typical antipsychotic drugs can include extrapyramidal side effects, such as rigidity, persistent muscle spasms, tremors, restlessness, and tardive dyskinesia.
  • Atypical antipsychotics include, but are not limted to, asenapine, olanzapine, clozapine, risperidone, sertindole, quetiapine, aripiprazole, amisulpride, ziprasidone, and paliperidone.
  • the patient is first treated with a typical antipsychotic prior to being treated with SNP.
  • the patient is first treated with SNP prior to being treated with a typical antipsychotic drug.
  • the patient is first treated with an atypical antipsychotic prior to being treated with SNP.
  • the patient is first treated with SNP prior to being treated with an atypical drug.
  • kits preferably contains an NO donor, more preferably SNP, and instructions for the use thereof.
  • compositions of the present invention are included in a container, pack, or dispenser together with instructions for administration.
  • Second generation 5 50.0% 8 80.0%
  • the subjects were monitored automatically with a heart monitor Dixtal 2020 and had ECG, blood pressure and oxygen levels measured through the experimental sessions. Safety and tolerability of the drug treatment were assessed clinically.
  • Nipride® Sodium Nitroprusside
  • PLB groups in the physiological parameters (systolic blood pressure, diastolic blood pressure, oxygen level and heart rate) evaluated at baseline, 60 minutes, 120 minutes, 180 minutes, and 240 minutes and analyzed by mean of a repeated measure ANOVA considering drug and time as factors.
  • NMDA receptor-NO-cGMP pathway Two studies investigated the effect of drugs that directly affect the NMDA receptor-NO-cGMP pathway.
  • Deutsch et al. 16 reported that methylene blue added to antipsychotic treatment produced an improvement in chronic schizophrenics as measured by the Clinical Global Impression scale (CGI), but not by the BPRS and the Schedule for the Assessment of Negative Symptoms (SANS).
  • Goff et al 17 studied the effects of sildenafil (a phosphodiesterase-5 inhibitor), added to an antipsychotic drug regimen, on cognition and psychopathology of patients with schizophrenia using BPRS, the Hopkins verbal learning test (HVLT) and the logical memory test (LMT), but found no difference from PLB.
  • sildenafil a phosphodiesterase-5 inhibitor
  • SNP could produce its effects by a number of different mechanisms. While not wishing to be bound by theory, the vasomotor effect of SNP could promote better cerebral perfusion or some other vascular effect modulated by NO. This possibility is unlikely, since both groups (PLB and SNP) did not differ in their physiological parameters.
  • Nitricoxide modulates NMDA- induced increases in intracellular Ca2+ in cultured rat forebrain neurones. Brain Res 592, 310-316.
  • Liddle PF and Morris D Schizophrenic syndromes and frontal lobe performance. Br.
  • Elevated endogenous nitric oxide synthase inhibitor in schizophrenic plasma may reflect abnormalities in brain nitric oxide production. Neurosci. Lett, 215(3): 209-1 1 , 1996.

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)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des compositions et des procédés pour le traitement de la schizophrénie chez un patient. Les compositions comprennent un donneur de NO et les procédés mettent en jeu l'administration d'un donneur de NO à un patient.
PCT/CA2011/000581 2010-05-21 2011-05-19 Compositions et procédés de traitement de la schizophrénie Ceased WO2011143755A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US34709010P 2010-05-21 2010-05-21
US61/347,090 2010-05-21

Publications (1)

Publication Number Publication Date
WO2011143755A1 true WO2011143755A1 (fr) 2011-11-24

Family

ID=44991125

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2011/000581 Ceased WO2011143755A1 (fr) 2010-05-21 2011-05-19 Compositions et procédés de traitement de la schizophrénie

Country Status (1)

Country Link
WO (1) WO2011143755A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019073045A1 (fr) * 2017-10-12 2019-04-18 Bdd Berolina Drug Development Gmbh Utilisation de donneurs de no
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12329862B2 (en) 2018-06-20 2025-06-17 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12485099B2 (en) 2016-12-20 2025-12-02 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BERNSTEIN ET AL.: "The many faces of nitric oxide in schizophrenia. A review", SCHIZOPHRENIA RESEARCH, vol. 78, 2005, pages 69 - 86 *
BUJAS-BOBANOVIC ET AL.: "Blockade of phencyclidine-induced effects by a nitric oxide donor", BRITISH JOURNAL OF PHARMACOLOGY, vol. 130, 2000, pages 1005 - 1012 *
KANE ET AL.: "Pharmacologic treatment of schizophrenia", DIALOGUES CLIN NEUROSCI., vol. 12, no. 3, 2010, pages 345 - 357 *
KIM ET AL.: "Decreased plasma nitric oxide metabolite levels in schizophrenia", PSYCHIATRY INVEST, vol. 3, no. 2, 2006, pages 57 - 62 *
PITSIKAS ET AL.: "Nitric oxide donor molsidomine attenuates psychotomimetic effects of the NMDA receptor antagonist MK-801", JOURNAL OF NEUROSCIENCE RESEARCH, vol. 84, 2006, pages 299 - 305 *
ROWLEY ET AL.: "Current and novel approaches to the drug treatment of schizophrenia", JOURNAL OF MEDICINAL CHEMISTRY, vol. 44, no. 4, 2001, pages 477 - 501 *
TANELI ET AL.: "Serum nitric oxide metabolite levels and the effect of antipsychotic therapy in schizophrenia", ARCHIVES OF MEDICAL RESEARCH, vol. 35, 2004, pages 401 - 405 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US10980753B2 (en) 2016-12-20 2021-04-20 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US12138353B2 (en) 2016-12-20 2024-11-12 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12485099B2 (en) 2016-12-20 2025-12-02 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
WO2019073045A1 (fr) * 2017-10-12 2019-04-18 Bdd Berolina Drug Development Gmbh Utilisation de donneurs de no
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12329862B2 (en) 2018-06-20 2025-06-17 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

Similar Documents

Publication Publication Date Title
Takahashi Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit
WO2011143755A1 (fr) Compositions et procédés de traitement de la schizophrénie
Alda et al. Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study
EP1073432B1 (fr) Utilisation de la d-alanine ou de la d-serine pour le traitement de la schizophrenie
Omar et al. Therapeutic effects of inorganic nitrate and nitrite in cardiovascular and metabolic diseases
US8629105B2 (en) Pharmaceutical compositions for the treatment of movement disorders
JP5902148B2 (ja) 自閉症治療用ジメチルスルホキシド（ｄｍｓｏ）製剤
US20100331415A1 (en) Use of omega-3-fatty acid(s)
AU2006208630B2 (en) SPM 927 for add-on therapy of schizophrenia
Riggs et al. (R, S)-ketamine and (2 R, 6 R)-hydroxynorketamine differentially affect memory as a function of dosing frequency
WO2012024293A2 (fr) Aliments thérapeutiques destinés au traitement de troubles neuropsychiatriques basés sur le développement, via la modulation des voies du glutathion et de la glycine dans le cerveau
US20100029771A1 (en) Treatment of addictive disorders
Uzbay et al. Effects of fluoxetine on ethanol withdrawal syndrome in rats
Horowitz et al. Nitroglycerine/N-acetylcysteine in the management of unstable angina pectoris
Crippen Life-threatening brain failure and agitation in the intensive care unit
RU2468813C1 (ru) Средство для профилактики или лечения острых и хронических нарушений мозгового кровообращения, применение и способ лечения
Kondo et al. A study of the therapeutic spectrum of a fixed‐dose of zotepine and its relationship with serum concentrations of the drug
Gianessi et al. A Thermostable Micellar Formulation of Rapalogs for Intracerebroventricular Delivery and the Therapy of Neurological Disorders
Bryan An Overview of Nitrite and Nitrate: New Paradigm of Nitric Oxide
US8927600B2 (en) Compound for use in the treatment of peripheral neuropathies
Quinones et al. Modulating mental fatigue: use of creatine, caffeine, or ketones
US11331319B2 (en) Combination treatment for neuropsychiatric disorders
IT202200021597A1 (it) Composizione per il trattamento dei disturbi neurocognitivi lievi e della demenza
JPH01197485A (ja) 恐慌状態の予防または断絶のための薬剤
Agent PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11782812

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11782812

Country of ref document: EP

Kind code of ref document: A1