WO2002098421A1 - Nouveau traitement pour affections neurologiques et psychiatriques - Google Patents

Nouveau traitement pour affections neurologiques et psychiatriques Download PDF

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Publication number
WO2002098421A1
WO2002098421A1 PCT/US2002/017579 US0217579W WO02098421A1 WO 2002098421 A1 WO2002098421 A1 WO 2002098421A1 US 0217579 W US0217579 W US 0217579W WO 02098421 A1 WO02098421 A1 WO 02098421A1
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WIPO (PCT)
Prior art keywords
disorder
aldose reductase
reductase inhibitor
group
disease
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PCT/US2002/017579
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English (en)
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William T. Regenold
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University Of Maryland, Baltimore
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Publication of WO2002098421A1 publication Critical patent/WO2002098421A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • This invention relates to the use of aldose reductase inhibitors to treat psychiatric and neurological disorders and diseases.
  • Related Art Abnormal glucose metabolism has long been suspected as an underlying pathophysiologic mechanism of mood disorders (Kooy F.H., Hyperglycemia in Mental Disorders, Brain, 42:214-289 (1919); Goodwin and Jamison, Manic-depressive Illness, Oxford University Press, New York (1990)). More recently, glucose intolerance (Mueller, et al., Intravenous Glucose Tolerance Test in Depression, Arch. Gen.
  • Hickie et al Hickie, et al., Subcortical Hyperintensities on Magnetic Resonance Imaging: Clinical Correlates and Prognostic Significance in Patients With Severe Depression, Biol. Psychiatry, 37(3): 151- 60 (1995)
  • in a study of 39 older (mean age of 64 years) depressed (32 unipolar and seven bipolar) inpatients report that multiple regression analysis of potential clinical predictors of WMHs including cerebrovascular risk factors such as hypertension and history of previous cerebrovascular disease, revealed that only patient age and family history of affective disorder predicted the occurrence of MRI T2-weighted WMHs.
  • Dupont et al (Dupont, et al., Psychiatry Res., 21(4):357-8 (1987); Dupont, et al., Subcortical Abnormalities Detected in Bipolar Affective Disorder Using Magnetic Resonance Imaging: Clinical and Neuropsychological Significance, Arch. Gen. Psychiatry, 47(l):55-9 (1990)) report a positive correlation with number of previous hospitalizations in bipolar patients, and Hickie et al (Hickie, supra) report a negative correlation with treatment response to both pharmacotherapy and electroconvulsive therapy in older unipolar patients.
  • peripheral neuropathy is a risk factor for depression in diabetics
  • peripheral neuropathy is also a risk factor for WMHs in diabetics. WMHs have been reported in 69% of diabetics with peripheral neuropathy compared to 12% in age-matched normal controls (Dejgaard, supra).
  • Nervous tissue is particularly vulnerable to increased polyol pathway activity, because it does not require insulin for transport of glucose into the cell (Greene, D.A., and Winegrad, A.I., Effects of Acute Experimental Diabetes on Composite Energy Metabolism in Peripheral Nerve Axons and Schwann Cells, Diabetes, 30(11):967-74 (1981)). Therefore, during hyperglycemia, glucose concentration equilibrates across the cell membrane resulting in high intracellular concentrations that mirror concentrations in the extracellular compartment. High intracellular glucose concentrations result in increased intracellular conversion of glucose to sorbitol through the polyol pathway.
  • oxidative stress and nerve ischemia can occur with increased polyol pathway activity, because of the depletion of NADPH and NAD+ which also serve as cofactors, respectively, for glutathione reductase, a free radical scavenging enzyme, and for endoneurial nitric oxide synthase, a vasodilatory enzyme important for microvascular function (Low, et al., The Roles of Oxidative Stress and Antioxidant Treatment in Experimental Diabetic Neuropathy, Diabetes, A6 Suppl. 2:S38-42 (1997)).
  • sorbitol concentration has been associated with depletion of myoinositol, resulting in a myoinositol-related defect in nerve sodium-potassium adenosine triphosphatase (ATPase) with subsequent slowing of nerve conduction in diabetic animals (Greene, et al, Sorbitol, Phosphoinositides, and Sodium-Potassium- ATPase in the Pathogenesis of Diabetic Complications, N. Engl. J. Med, 316(10):599-606 (1987)).
  • ATPase nerve sodium-potassium adenosine triphosphatase
  • aldose reductase inhibitors can be used to treat psychiatric disorders or disease and/or neurological diseases or disorders in animals or humans.
  • Administration of aldose reductase inhibitors to a human or animal having a psychiatric disorder or disease and/or neurological diseases or disorders will prevent the accumulation of sorbitol and thus treat the disease or disorder or lessen the symptoms of the disease or disorder.
  • These diseases or disorders includes, but are not limited to, bipolar disorder, major depression, schizoaffective disorder, schizophrenia, dementia of elderly, affective psychoses, episodic Axis II psychotic conditions, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer disease.
  • aldose reductase inhibitors can prevent the build-up of sorbitol in animals or human having neurological diseases or disorders and psychiatric diseases or disorders.
  • sorbitol in the brain and central nervous system and peripheral nervous system of animals or humans having neurological diseases or disorders and psychiatric diseases or disorders will help treat those diseases or disorders and/or alleviate the symptoms of those diseases or disorders and psychiatric diseases or disorders.
  • diseases or disorders includes, but are not limited to, bipolar disorder, major depression, schizoaffective disorder, schizophrenia, dementia of elderly, affective psychoses, episodic Axis II psychotic conditions, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer disease.
  • diseases or disorders includes, but are not limited to, bipolar disorder, major depression, schizoaffective disorder, schizophrenia, dementia of elderly, affective psychoses, episodic Axis II psychotic conditions, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer disease.
  • the psychiatric disorders or disease and/or neurological diseases or disorder include, but are not limited to, bipolar disorder, major depression, schizoaffective disorder, schizophrenia, dementia of elderly, affective psychoses, episodic Axis II psychotic conditions, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer disease.
  • Compounds which prevents or inhibits sorbitol accumulation can be aldose reductase inhibitors.
  • aldose reductase inhibitors useful in this invention include, but are not limited to, alrestatin, sorbinil, N-4-(benzoylamino)phenylsulfonyl glycine, zenarestat, tolrestat, fidarestat, ponalrestat, epalrestat, GP-1447, ONO-2235, CT-112, WAY-121,509, and 3-(arylmethyl)-2,4,5-trioxoimidazolidine-l-acetic acid.
  • aldose reductase inhibitors to treat psychiatric disorders or neurological diseases in humans and animals.
  • aldose reductase inhibitors exist. A partial listing of these compounds include alrestatin, sorbinil, N-4-(benzoylamino)phenylsulfonyl glycine, zenarestat, tolrestat, fidarestat, ponalrestat, epalrestat, GP-1447, ONO-2235, CT-112, WAY-121,509, IDD 598, and 3-(arylmethyl)-2,4,5-trioxoimidazolidine-l -acetic acid.
  • Aldose reductase inhibitors can be administered by any method. It is preferable to administer aldose reductase inhibitors orally, and via the following modes of injections: intravenous, intramuscular, intraspinal, intrameningeal, intracranial, and intrathecal. It is more preferable to administer aldose reductase inhibitors orally.
  • pharmaceutically acceptable carrier means a chemical composition with which the active ingredient may be combined and which, following the combination, can be used to administer the active ingredient to a subject.
  • physiologically acceptable ester or salt means an ester or salt form of the active ingredient which is compatible with any other ingredients of the pharmaceutical composition, which is not deleterious to the subject to which the composition is to be administered.
  • compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.
  • pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts.
  • compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation.
  • Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, and other mammals.
  • compositions that are useful in the methods of the invention may be prepared, packaged, or sold in formulations suitable for parenteral, topical, pulmonary, intranasal, buccal, ophthalmic, intrathecal, intraspinal, intrameningeal, intracranial, or another route of administration.
  • a pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses.
  • a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline.
  • Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration.
  • injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative.
  • Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents.
  • the active ingredient is provided in dry (i.e. powder or granular) form for reconstitution with a suitable vehicle (e.g. sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.
  • compositions of the invention formulated for pulmonary delivery may also provide the active ingredient in the form of droplets of a solution or suspension.
  • Such formulations may be prepared, packaged, or sold as aqueous or dilute alcoholic solutions or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration preferably have an average diameter in the range from about 0.1 to about 200 nanometers.
  • parenteral administration of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like.
  • parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal, intraspinal, intrameningeal, intracranial injections, and kidney dialytic infusion techniques.
  • CNS disorders for this invention, include bipolar disorder, major depression, schizoaffective disorder, schizophrenia, dementia of elderly, affective psychoses, episodic Axis II psychotic conditions, multiple sclerosis, and Alzheimer disease. (ALS affects the peripheral nervous system.)
  • the amount of aldose reductase inhibitor to be administered depends on the particular compound used.
  • indicia include, but are not limited to, the amount of the compound in the CSF and the amount of sorbitol in the CSF.
  • the amount of compound in the CSF depends, in part, on the drug's ability to cross the blood-brain- barrier and enter the CNS (if the drug is not directly administered into the CSF or brain).
  • fidarestat SNK 860
  • the dosage administered orally can range from 500 ⁇ g/day to 1000 mg/day.
  • a preferable dosage of fidarestat to achieve the desired CNS concentration is in the range of 20 mg/liter/day to 800 mg/liter/day but can range from 1 mg/liter/day to 20 g/liter/day.
  • the dosage administered will be less than the dosage administered orally or intramuscularly.
  • the preferred dosage of fidarestat is less than the preferred dosage for CNS disorders because ALS is primarily a periperal nervous system disorder.
  • a preferred dosage range is 1 mg and 40 mg per day but can range from 500 ⁇ g to 1000 mg per day.
  • Aldose reductase inhibitors can be used to treat psychiatric disorders in humans and in animals.
  • the particular psychiatric disorders include, but are not limited to, bipolar disorder, major depression, schizoaffective disorder, schizophrenia, dementia of elderly, affective psychoses (such as mania and psychotic depression), and episodic Axis II psychotic conditions.
  • Aldose reductase inhibitors may also be useful in treating neurodevelopmental disorders, such as but not limited to, autism, mental retardation, and subclinical or latent psychosis.
  • aldose reductase inhibitors may be used to treat multiple sclerosis, amyotrophic lateral sclerosis (ALS), and other neurodegenerative diseases. Diabetes may be present in the patients or animals having these psychiatric disorders and diseases, neurodevelopmental disorders and diseases, and neurodenerative disorders and diseases, and other conditions.
  • ALS amyotrophic lateral sclerosis
  • the mean age for the patients are 42.3 ( ⁇ 12) years for MS Prog, 39.6 ( ⁇ 8) years for MS RR; and 38.8 ( ⁇ 12) years for control patients. Three-fourths of the patients are female, and all are white.
  • psychiatric disease diagnosis and rating scales are administered to determine level of symptoms (e.g., for depression: Hamilton Depression Scale; for bipolar disorder: HAM-D or Young Mania Scale; for, all disorders: Brief Psychiatric Rating Scale (BPRS)).
  • level of symptoms e.g., for depression: Hamilton Depression Scale; for bipolar disorder: HAM-D or Young Mania Scale; for, all disorders: Brief Psychiatric Rating Scale (BPRS)).
  • BPRS Brief Psychiatric Rating Scale
  • Rating scales are administered biweekly for 6 months. Sorbitol levels in blood are determined biweekly. Sorbitol levels in the CSF are assessed at the beginning and end of treatment. Patients undergo another MRI at the end of six months for comparison with first MRI for assessment of effect on white matter disease.
  • psychiatric subjects treated with fidarestat should show a greater improvement or stabilization of their disorders as indicated by the following: Depressed subjects treated with an aldose reductase inhibitor (ART) will have a greater reduction in HDRS score, on average, from a score of 25 to 10 points compared to placebo-treated subjects. Manic subjects treated with an aldose reductase inhibitor (ART) will have a greater reduction in YMRS score, on average, from a score of 40 to 10 points compared to placebo-treated subjects.
  • ART aldose reductase inhibitor
  • the CSF sorbitol concentrations prior to treatment should range from approximately 20 ⁇ moles/liter to 100 ⁇ moles/liter.
  • the CSF sorbitol concentrations should range from approximately >1 ⁇ moles/liter to 30 ⁇ moles/liter. This reduction in CSF sorbitol concentrations demonstrates the effective inhibition of aldose reductase in the CNS.
  • Example 2 [38] In a placebo-controlled, double-blind study lasting 6 months, patients with any of the following disorders are recruited: multiple sclerosis (MS), amyotrophic lateral sclerosis, and Alzheimer disease, with or without diabetes comorbidity.
  • MS multiple sclerosis
  • amyotrophic lateral sclerosis Alzheimer disease
  • Fifty patients are randomized to placebo, 20 mg per day of fidarestat, or 40 mg per day of fidarestat. Patients take the medication and placebo orally. All patients have blood sorbitol and cerebral spinal fluid (CSF) sorbitol levels measured. Patients also have an MRI to assess white matter hyperintensities.
  • CSF cerebral spinal fluid
  • assessments include Clinical Global Impression (CGI), Mini-Mental State Exam (MMSE), the ADAS-Cog scale, and the Neuropsychiatiric Inventory (NPI).
  • CGI Clinical Global Impression
  • MMSE Mini-Mental State Exam
  • NPI Neuropsychiatiric Inventory
  • MS patients the assessments include Kurtzke's Expanded Disability Status Scale (EDSS), the SF-36 - Short form 36, Ashworth Spasticity Scale, Mini-Mental State Exam (MMSE), and the Neuropsychiatiric Inventory (NPI).
  • EDSS Kurtzke's Expanded Disability Status Scale
  • SF-36 - Short form 36 the SF-36 - Short form 36
  • Ashworth Spasticity Scale Mini-Mental State Exam
  • NPI Neuropsychiatiric Inventory
  • assessments include the SF-36 - Short form 36, quantitative myometry, forced vital capacity measurement, ALS Functional Rating Scale, and the Ashworth Spasticity Scale.
  • Sorbitol levels in the CSF are assessed at the beginning and end of treatment. Patients undergo another MRI at the end of six months for comparison with first MRI for assessment of effect on white matter disease. [41] At the end of six months, all patients are assessed for an improvement of clinical symptoms, decreased MRI evidence of brain white matter hyperintensities, and decreased sorbitol levels in the CSF and blood.
  • the neurologic subjects treated with fidarestat should show a greater improvement or stabilization of their disorders as indicated by the following: MS subjects treated with an aldose reductase inhibitor (ART) will have a greater increase in Kurtzke's Expanded Disability Status Scale (EDSS), on average, from a score of 3 points to 4 points, a greater increase in MMSE, on average, from a score of 24 points to 26 points, a greater decrease in Ashworth Spasticity Scale score, on average, from a score of 4 points to 2 points, and a greater increase in the SF- 36 score, on average, from a score of 40 points to 60 points, compared to placebo-treated subjects.
  • EDSS Kurtzke's Expanded Disability Status Scale
  • Alzheimer subjects treated with an aldose reductase inhibitor will have a greater reduction in NPI score, on average, from a score of 30 points to 20 points, a greater increase in MMSE, on average, from a score of 20 points to 22 points, and a greater decrease in CGI score, on average, from a score of 4 points to 2 points compared to placebo-treated subjects.
  • ARI aldose reductase inhibitor
  • ALS subjects treated with an aldose reductase inhibitor will have a greater reduction in the Ashworth Spasticity Scale score, on average, from a score of 4 points to 2 points, a greater increase in the ALS Functional Rating Scale, on average, from a score of 20 points to 30 points, a greater increase in the SF-36 score, on average, from 40 points to 60 points, and a greater percentage of subjects with improvements in forced vital capacity and maximal voluntary isometric muscular contraction (MVIC) of the knee and elbow joints compared to placebo-treated subjects.
  • MVIC maximal voluntary isometric muscular contraction

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Abstract

La présence de sorbitol dans le liquide céphalo-rachidien de patients souffrant de maladies ou affections psychiatriques ou de maladies ou affections neurologiques est connue. L'utilisation de composés pour prévenir l'accumulation de sorbitol dans le système nerveux central et dans le cerveau de ces patients est utile pour le traitement de ces maladies et affections. Les inhibiteurs d'aldose réductase constituent un type de composé utile pour prévenir l'accumulation de sorbitol. On peut en outre administrer des inhibiteurs d'aldose réductase pour prévenir ces maladies ou affections et pour atténuer les symptômes de ces maladies et affections. Les types de maladies et affections psychiatriques que l'on peut ainsi traiter ou prévenir sont notamment les troubles bipolaires, la dépression majeure, les troubles schizoaffectifs, la schizophrénie, la démence sénile, les psychoses affectives et les états psychotiques d'axe II épisodiques. Les types de maladies et affections neurologiques que l'on peut ainsi traiter ou prévenir sont notamment la sclérose en plaques, la sclérose latérale amyotrophique et la maladie d'Alzheimer.
PCT/US2002/017579 2001-06-05 2002-06-05 Nouveau traitement pour affections neurologiques et psychiatriques WO2002098421A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015057175A1 (fr) 2013-10-15 2015-04-23 Ústav Experimentálnej Farmakológie A Toxikológie Sav Utilisation de 5-carboxyméthyl-3-mercapto-1,2,4-triazino-[5,6-b]indoles et leur composition pharmaceutique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4970214A (en) * 1986-06-27 1990-11-13 Nippon Shinyaku Co., Ltd. Quinoline substituted oxomethyl or thioxomethyl glycine derivatives and aldose reductase inhibition therewith
US5055481A (en) * 1989-03-24 1991-10-08 Wakamoto Pharmaceutical Co., Ltd. Tetrazole derivatives and aldose reductase inhibition therewith
US6127367A (en) * 1996-02-29 2000-10-03 Pfizer, Inc. Method of reducing tissue damage associated with non-cardiac ischemia

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4970214A (en) * 1986-06-27 1990-11-13 Nippon Shinyaku Co., Ltd. Quinoline substituted oxomethyl or thioxomethyl glycine derivatives and aldose reductase inhibition therewith
US5055481A (en) * 1989-03-24 1991-10-08 Wakamoto Pharmaceutical Co., Ltd. Tetrazole derivatives and aldose reductase inhibition therewith
US6127367A (en) * 1996-02-29 2000-10-03 Pfizer, Inc. Method of reducing tissue damage associated with non-cardiac ischemia

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015057175A1 (fr) 2013-10-15 2015-04-23 Ústav Experimentálnej Farmakológie A Toxikológie Sav Utilisation de 5-carboxyméthyl-3-mercapto-1,2,4-triazino-[5,6-b]indoles et leur composition pharmaceutique

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